Novel urea  and thiourea derivatives

ABSTRACT

The present application discloses compounds of formula (I) wherein X is ═O, ═S, ═NH, ═NOH and ═NO-Me; A is —C(═O)—, —S(═O) 2 —, —C(═S)— and P(═O)(R 5 )—; B is, —O—, —(CH 2 ) 3-6 —, and O—(CH 2 ) 2-5 —; D is, —O—, —CR 7 R 8 — and —NR 9 ; m is 0-12, n is 0-12, m+n is 1-20; p is 0-4; R 1  is opt.sub. heteroaryl; and pharmaceutically acceptable salts thereof, and prodrugs thereof. The application also discloses the compound for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT), e.g. inflammatory and tissue repair disorders; dermatosis; autoimmune diseases, Alzheimers disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telengiectasia.

FIELD OF THE INVENTION

This invention relates to urea and thiourea derivatives, which areuseful for the inhibiting of the enzyme nicotinamidephosphoribosyltransferase (NAMPRT), and to medical use of suchderivatives.

BACKGROUND OF THE INVENTION

Inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT)results in the inhibition of NF-kB, the inhibition of NF-kB being aresult of the lowering of cellular concentrations of nicotinamideadenine dinucleotide (NAD) (Beauparlant et al. (2007) AACR-NCI-EORTCInternational Conference on Molecular Targets and Cancer Therapeutics,2007 Oct. 22-26 Abstract nr A82; and Roulson et al. (2007)AACR-NCI-EORTC International Conference on Molecular Targets and CancerTherapeutics, 2007 Oct. 22-26 Abstract nr A81).

Tumor cells have elevated expression of NAMPRT and a high rate of NADturnover due to high ADP-ribosylation activity required for DNA repair,genome stability, and telomere maintenance making them more susceptibleto NAMPRT inhibition than normal cells. This also provides a rationalefor the use of compounds of this invention in combination with DNAdamaging agents for future clinical trials.

The pathways of NAD biosynthesis are shown in FIG. 1.

NAMPRT is involved in the biosynthesis of nicotinamide adeninedinucleotide (NAD) and NAD(P). NAD can be synthesized in mammalian cellsby three different pathways starting either from tryptophan viaquinolinic acid, from nicotinic acid (niacin) or from nicotinamide(niacinamide).

Quinolinic acid reacts with phosphoribosyl pyrophosphate to form niacinmononucletide (dNAM) using the enzyme quinolinic acidphosphoribosyltransferase

which is found in liver kidney and brain.

Nicotinic acid (niacin) reacts with PRPP to form niacin mononucleotide(dNAM), using the enzyme niacin phosphoribosyltransferase

which is widely distributed in various tissues.

Nicotinamide (niacinamide) reacts with PRPP to give niacinamidemononucleotide (NAM) using the enzyme nicotinamidephosphoribosyltransferase (NAMPRT)

which is also widely distributed in various tissues.

The subsequent addition of adenosine monophosphate to themononucleotides results in the formation of the correspondingdinucleotides: Niacin mononucleotide and niacinamide mononucleotidereact with ATP to form niacin adenine dinucleotide (dNAD) andniacinamide adenine dinucleotide (NAD) respectively. Both reactions,although they take place on different pathways, are catalysed by thesame enzyme, NAD pyrophosphorylase

.

A further amidation step is required to convert niacin adeninedinucleotide (dNAD) to niacinamide adeinine dinucleotide (NAD) Theenzyme which catalyses this reaction is NAD synthetase

. NAD is the immediate precursor of niacinamide adenine dinucleotidephosphate (NAD(P)) The reaction is catalysed by NAD kinase. For detailssee, e.g., Cory J. G. Purine and pyrimidine nucleotide metabolism In:Textbook of Biochemistry and Clinical Correlations 3^(rd) edition ed.Devlin, T, Wiley, Brisbane 1992, pp 529-574.

Normal cells can typically utilize both precursors niacin andniacinamide for NAD(P) synthesis, and in many cases additionallytryptophan or its metabolites. Accordingly, murine glial cells useniacin, niacinamide and quinolinic acid (Grant et al. (1998) J.Neurochem. 70: 1759-1763). Human lymphocytes use niacin and niacinamide(Carson et al. (1987) J. Immunol. 138: 1904-1907; Berger et al. (1982)Exp. Cell Res. 137; 79-88). Rat liver cells use niacin, niacinamide andtryptophan (Yamada et al. (1983) Int. J. Vit. Nutr. Res. 53: 184-1291;Shin et al. (1995) Int. J. Vit. Nutr. Res. 65: 143-146; Dietrich (1971)Methods Enzymol. 18B; 144-149). Human erythrocytes use niacin andniacinamide (Rocchigiani et al. (1991) Purine and pyrimidine metabolismin man VII Part B ed. Harkness et al. Plenum Press New York pp337-3490). Leukocytes of guinea pigs use niacin (Flechner et al. (1970),Life Science 9: 153-162).

NAD(P) is involved in a variety of biochemical reactions which are vitalto the cell and have therefore been thoroughly investigated. The role ofNAD(P) in the development and growth of tumours has also been studied.It has been found that many tumour cells utilize niacinamide forcellular NAD(P) synthesis. It is thought that niacin and tryptophanwhich constitute alternative precursors in many normal cell types cannotbe utilized in tumour cells, or at least not to an extent sufficient forcell survival. Selective inhibition of an enzyme which is only on theniacinamide pathway (such as NAMPRT) would constitute a method for theselection of tumour specific drugs. This is exemplified by the NAMPRTinhibitors which have been in clinical trials as anti cancer agents,namely FK866/AP0866, (see Hasmann and Schemainda, Cancer Res63(21):7463-7442.), CHS828/GMX1778 and its prodrug EB1627/GMX1777 (seeHjarnaa et al, Cancer Research 59; 5751-5757; Binderup et al, Bioorg MedChem Lett 15:2491-2494). Further inhibitors of NAMPRT are found in WO2006/066584, WO 2003/097602, WO 2003/097601, WO 2002/094813, WO2002/094265, WO 2002/042265, WO 2000/61561, WO2000/61559, WO1997/048695, WO 1997/048696, WO 1997/048397, WO 1999/031063, WO1999/031060 and WO 1999/031087.

It is known that various derivatives of urea, substituted in a specificmanner have pharmacologically useful properties. In particular, certainderivatives are known to possess therapeutic activity. All of thesecompounds however are structurally dissimilar from the compounds of thepresent invention.

Compounds comprising urea moieties are described in the followingpublications:

Budd et al. (WO 2007/068473) describe the following compound as aninhibitor of PI-3-kinase:

Bruce et al. (WO 2008/000421) describe compounds of the followingstructure as inhibitors of PI-3 kinase delta:

Further inhibitors of PI-3 kinase are described by Budd et al. (WO2007/134827):

Weber et al. (DE 2614189) describe compounds of the following genericstructure as analgesic agents.

Ashwell et al. (2009) [WO 2009/026446] describe the following compoundsas inhibitors of histone deacetylases:

The following compounds are listed in the Ambinter Stock ScreeningCollection of 20 Feb. 2009:

Fitzmaurice et al (2007) describe the following compound's properties inpolar solvents [Organic & Biomolecular Chemistry (2007) 5(11) 1706-1714]

Morio et al (1998) [European patent application EP283040] describe thefollowing compound for use in photographic material:

Inoue et al (1998) [EP 283041] describe the following compound for usein photographic material:

Schoue et al (1998) [WO 1998/54144] describe the following compound as apotential inhibitor of cell proliferation:

BRIEF DESCRIPTION OF THE INVENTION

It is believed that the novel compounds of the invention are acting onthe enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and that thedown-stream inhibition of NF-kB is the result of the lowering ofcellular concentrations of nicotinamide adenine dinucleotide (NAD).

Hence, the present invention provides compounds of the general formula(I) according to claim 1, and the utilization of these compounds inmedicine, cf. claims 18, 19, 21 and 22.

Inhibitors of the enzyme NAMPRT may be used in the treatment of cancer(WO 97/48696), to cause immunosuppression (WO 97/48397), for thetreatment of diseases involving angiogenesis (WO 2003/80054), for thetreatment of rheumatoid arthritis or septic shock (WO 2008/025857), orfor the prophylaxis and treatment of ischaemia (EP 08102310.3(unpublished application)).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the pathway of NAD biosynthesis (from Biedermann E.et al, WO 00/50399).

DETAILED DESCRIPTION OF THE INVENTION Compounds of the Invention

The present invention i.a. relates to particular urea and thioureaderivatives which are useful for the inhibition of the enzymenicotinamide phosphoribosyltransferase (NAMPRT).

The present invention relates to compounds of the formula (I)

whereinX is selected from ═O, ═S, ═NH, ═NOH and ═NO-Me;A is selected from —C(═O)—, —S(═O)₂—, —C(═S)— and —P(═O)(R⁵)—, whereinR⁵ is selected from C₁₋₆-alkyl, C₁₋₆-alkoxy and hydroxy;B is selected from a single bond, —(CH₂)₃₋₆—, —O—, and —O—(CH₂)₂₋₅—;D is selected from a single bond, —O—, —CR⁷R⁸— and —NR⁹, wherein R⁷, R⁸and R⁹ are independently selected from hydrogen, optionally substitutedC₁₋₁₂-alkyl, optionally substituted C₁₋₁₂-alkenyl, optionallysubstituted aryl, optionally substituted heterocyclyl, and optionallysubstituted heteroaryl;m is an integer of 0-12 and n is an integer of 0-12, wherein the sum m+nis 1-20;p is an integer of 0-4;R¹ is selected from optionally substituted heteroaryl;R² is selected from hydrogen, optionally substituted C₁₋₁₂-alkyl,optionally substituted C₃₋₁₂-cycloalkyl, —[CH₂CH₂O]₁₋₁₀-(optionallysubstituted C₁₋₆-alkyl), optionally substituted C₁₋₁₂-alkenyl,optionally substituted aryl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl; and R³ is selected from optionallysubstituted C₁₋₁₂-alkyl, optionally substituted C₃₋₁₂-cycloalkyl,—[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl), optionallysubstituted C₁₋₁₂-alkenyl, optionally substituted aryl, optionallysubstituted heterocyclyl, and optionally substituted heteroaryl; or R²and R³ together with the intervening atoms (i.e. —N—B—) form anoptionally substituted N-containing heterocyclic or heteroaromatic ring;each of R⁴ and R⁴* is independently selected from hydrogen, optionallysubstituted C₁₋₁₂-alkyl and optionally substituted C₁₋₁₂-alkenyl;with the proviso that R¹ is not optionally substituted thiazol-2-yl whenp is 0;and with the proviso that the compound is notphenyl-NH—C(═O)—(CH₂)₅—NH—C(═S)—NH-(4-pyridyl); and pharmaceuticallyacceptable salts thereof, and prodrugs thereof.

In particular,

when X is ═O and A is —SO₂—, then B is —O— or —(CH₂)₃₋₆  or—O—(CH₂)₂₋₅—; andwhen X is ═O, A is —C(═O)—, and p=0, then B is —O— or —(CH₂)₃₋₆— or—O—(CH₂)₂₋₅—; andwhen X is ═O, A is —C(═O)—, and p=0, then R¹ is not

when X is ═O, A is —C(═O)—, and p=1-4, then R¹ is not

and when X is ═S, A is —C(═O)—, and p=1-4, then R³ is not benzyl or

DEFINITIONS

In the present context, the terms “C₁₋₁₂-alkyl” and “C₁₋₆-alkyl” areintended to mean a linear, cyclic or branched hydrocarbon group having 1to 12 carbon atoms and 1 to 6 carbon atoms, respectively, such asmethyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl,tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl.

Although the term “C₃₋₁₂-cycloalkyl” is encompassed by the term“C₁₋₁₂-alkyl”, it refers specifically to the mono- and bicycliccounterparts, including alkyl groups having exo-cyclic atoms, e.g.cyclohexyl-methyl.

Similarly, the terms “C₂₋₁₂-alkenyl” and “C₂₋₆-alkenyl” are intended tocover linear, cyclic or branched hydrocarbon groups having 2 to 12carbon atoms and 2 to 6 carbon atoms, respectively, and comprising (atleast) one unsaturated bond. Examples of alkenyl groups are vinyl,allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl.Preferred examples of alkenyl are vinyl, allyl, butenyl, especiallyallyl.

Although the term “C₃₋₁₂-cycloalkenyl” is encompassed by the term“C₂₋₁₂-alkenyl”, it refers specifically to the mono- and bicycliccounterparts, including alkenyl groups having exo-cyclic atoms, e.g.cyclohexenyl-methyl and cyclohexyl-allyl.

In the present context, i.e. in connection with the terms “alkyl”,“cycloalkyl”, “alkoxy”, “alkenyl”, “cycloalkenyl” and the like, the term“optionally substituted” is intended to mean that the group in questionmay be substituted one or several times, preferably 1-3 times, withgroup(s) selected from hydroxy (which when bound to an unsaturatedcarbon atom may be present in the tautomeric keto form), C₁₋₆-alkoxy(i.e. C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming a keto oraldehyde functionality), C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl,arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl,heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl,heteroarylcarbonylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylcarbonyloxy, heterocyclylaminocarbonyl,heterocyclylcarbonylamino, amino, mono- and di(C₁₋₆-alkyl)amino,—N(C₁₋₄-alkyl)₃ ⁺, carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkanoyloxy, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylsulphonyloxy, nitro, C₁₋₆-alkylthio, andhalogen, where any aryl, heteroaryl and heterocyclyl may be substitutedas specifically described below for aryl, heteroaryl and heterocyclyl,and any alkyl, alkoxy, and the like, representing substituents may besubstituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s).

Typically, the substituents are selected from hydroxy (which when boundto an unsaturated carbon atom may be present in the tautomeric ketoform), C₁₋₆-alkoxy (i.e. C₁₋₆-alkyloxy), C₂₋₆-alkenyloxy, carboxy, oxo(forming a keto or aldehyde functionality), C₁₋₆-alkylcarbonyl, formyl,aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroaryloxy,heteroarylamino, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylcarbonyl, amino, mono- anddi(C₁₋₆-alkyl)amino; carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,guanidino, carbamido, C₁₋₆-alkyl-sulphonyl-amino, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylthio, halogen, where any aryl,heteroaryl and heterocyclyl may be substituted as specifically describedbelow for aryl, heteroaryl and heterocyclyl.

In some embodiments, substituents are selected from hydroxy,C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen.

The term “halogen” includes fluoro, chloro, bromo, and iodo.

In the present context, the term “aryl” is intended to mean a fully orpartially aromatic carbocyclic ring or ring system, such as phenyl,naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl,benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferredexample.

The term “heteroaryl” is intended to mean a fully or partially aromaticcarbocyclic ring or ring system where one or more of the carbon atomshave been replaced with heteroatoms, e.g. nitrogen (═N— or —NH—),sulphur, and/or oxygen atoms. Examples of such heteroaryl groups areoxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,coumaryl, furanyl, thienyl, quinolyl, benzo-thiazolyl, benzotriazolyl,benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl,tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl,benzopyrazolyl, phenoxazonyl. Particularly interesting heteroaryl groupsare benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl,isoquinolyl, indolyl in particular benzimidazolyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, furyl, thienyl, quinolyl, tetrazolyl, andisoquinolyl.

The term “heterocyclyl” is intended to mean a non-aromatic carbocyclicring or ring system where one or more of the carbon atoms have beenreplaced with heteroatoms, e.g. nitrogen (═N— or —NH—), sulphur, and/oroxygen atoms. Examples of such heterocyclyl groups (named according tothe rings) are imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,azepane, azocane, aziridine, azirine, azetidine, pyrroline, tropane,oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, andhexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane,thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane,tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene,tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane,dioxepane, oxathiane, oxathiepane. The most interesting examples aretetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane,oxazepane, thiazolane, thiazinane, and thiazepane, in particulartetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane,oxazinane (morpholine), and thiazinane.

The term “N-containing heterocyclic or heteroaromatic ring” are intendedto encompass those mentioned under “heterocyclyl” and “heteroaryl”,respectively, which include one or more heteroatoms, at least one ofwhich begin a nitrogen atom. Examples hereof are piperazine, isoxazole,isoxazolidine, and morpholine, etc.

The term “N,O-containing heterocyclic or heteroaromatic ring” areintended to encompass those mentioned under “heterocyclyl” and“heteroaryl”, respectively, which include two or more heteroatoms, twoof which being neighbouring nitrogen and oxygen atoms. Examples hereofare isoxazole, isoxazolidine, morpholine, etc.

In the present context, i.e. in connection with the terms “aryl”,“heteroaryl”, “heterocyclyl”, “N,O-containing heterocyclic orheteroaromatic ring” and the like (e.g. “aryloxy”, “heteroarylcarbonyl”,etc.), the term “optionally substituted” is intended to mean that thegroup in question may be substituted one or several times, preferably1-5 times, in particular 1-3 times, with group(s) selected from hydroxy(which when present in an enol system may be represented in thetautomeric keto form), C₁₋₆-alkyl, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, oxo(which may be represented in the tautomeric enol form), oxide (onlyrelevant as the N-oxide), carboxy, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl,arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- anddi(C₁₋₆-alkyl)amino; carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulfonyl, mono-and di(C₁₋₆-alkyl)amino-sulfonyl, dihalogen-C₁₋₄-alkyl,trihalogen-C₁₋₄-alkyl, halogen, where aryl and heteroaryl representingsubstituents may be substituted 1-3 times with C₁₋₄-alkyl, C₁₋₄-alkoxy,nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the like,representing substituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidino.

Typically, the substituents are selected from hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, oxo (which may be represented in the tautomeric enol form),carboxy, C₁₋₆-alkylcarbonyl, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino; carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino, guanidino,carbamido, C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl, mono- anddi(C₁₋₆-alkyl)amino-sulfonyl or halogen, where any alkyl, alkoxy and thelike, representing substituents may be substituted with hydroxy,C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidino. In some embodiments, thesubstituents are selected from C₁₋₆-alkyl, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl,alkoxy and the like, representing substituents may be substituted withhydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino, halogen,C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidino.

Groups (e.g. R² and R³) including C₃₋₁₂-cycloalkyl, C₃₋₁₂-cycloalkenyland/or aryl as at least a part of the substituent are said to include “acarbocyclic ring”.

Groups (e.g. R² and R³) including heterocyclyl or heteroaryl as at leasta part of the substituent are said to include “a heterocyclic ring” and“a heteroaromatic ring”, respectively.

The term “pharmaceutically acceptable salts” is intended to include acidaddition salts and basic salts. Illustrative examples of acid additionsalts are pharmaceutically acceptable salts formed with non-toxic acids.Exemplary of such organic salts are those with maleic, fumaric, benzoic,ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, and nitric acids. Examples of basic salts aresalts where the (remaining) counter ion is selected from alkali metals,such as sodium and potassium, alkaline earth metals, such as calcium,and ammonium ions (N(R)₃R′, where R and R′ independently designatesoptionally substituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl,optionally substituted aryl, or optionally substituted heteroaryl).Pharmaceutically acceptable salts are, e.g., those described inRemington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.),Mack Publishing Company, Easton, Pa., U.S.A., 1985 and more recenteditions and in Encyclopedia of Pharmaceutical Technology. Thus, theterm “an acid addition salt or a basic salt thereof” used herein isintended to comprise such salts. Furthermore, the compounds as well asany intermediates or starting materials may also be present in hydrateform.

The term “prodrug” used herein is intended to mean a compound which—uponexposure to physiological conditions—will liberate a derivative saidcompound which then will be able to exhibit the desired biologicalaction. Typical examples are labile esters (i.e. a latent hydroxyl groupor a latent acid group).

Moreover, it should be understood that the compounds may be present asracemic mixtures or the individual stereoisomers such as enantiomers ordiastereomers. The present invention encompasses each and every of suchpossible stereoisomers (e.g. enantiomers and diastereomers) as well asracemates and mixtures enriched with respect to one of the possiblestereoisomers.

EMBODIMENTS

In one primary embodiment, X is selected from ═O and ═S.

In one embodiment hereof, X is ═O and B is —O—. Within one importantvariant of this embodiment A is —S(═O)₂—. Within another importantvariant of this embodiment, A is —C(═O)—.

In another embodiment X is ═S and B is —O—. Within one important variantof this embodiment A is —S(═O)₂—. Within another important variant ofthis embodiment, A is —C(═O)—.

In another embodiment, X is selected from ═O and ═S and B is a singlebond. Within one important variant of this embodiment A is —S(═O)₂—.Within another important variant of this embodiment, A is —C(═O)—.

In another embodiment, B is selected from —(CH₂)₃₋₆— and —O—(CH₂)₂₋₅—,preferably from —(CH₂)₃₋₄— and —O—(CH₂)₁₋₃—. Within this embodiment, Xis preferably selected from ═O and ═S.

In the above embodiments, D is preferably selected from a single bond,—O—, and —NR⁹. More particular, D is a single bond.

With respect to R¹, this substituent is preferably selected fromoptionally substituted pyridin-4-yl, optionally substitutedpyrimidin-4-yl, optionally substituted 1,2,4-triazin-3-yl, optionallysubstituted isoxazol-4-yl, optionally substituted pyrazin-2-yl, andoptionally substituted picolyl; in particular from pyridin-4-yl,pyrimidin-4-yl, 1,2,4-triazin-3-yl, 3,5-isoxazol-4-yl, pyrazin-2-yl, andpicolyl.

The distance between R¹ and the urea moiety is determined by p. p is aninteger of 0-4, but is preferably 0-2, in particular 0.

In a currently particularly interesting embodiment, p is 0 and R¹ ispyridin-4-yl.

In another particularly interesting embodiment, p is 1.

The length of the spacer element is defined by m and n. Preferably, m isan integer of 0-10 and n is an integer of 0-10, wherein the sum m+n is1-12; in particular m is an integer of 1-8 and n is an integer of 0-3,wherein the sum m+n is 3-8. In a currently most preferred variant, m isan integer of 2-8 and n is 0.

It appears that—besides D, A and B—R² and R³ (and in part also R⁴ andR⁴*) play an important role for the efficacy of the compounds of theinvention. Hence, in one particularly interesting embodiment, at leastone of R² and R³ includes a carbocyclic ring, heterocyclic ring or aheteroaromatic ring, or R² and R³ together with the intervening atomsform an optionally substituted N-containing heterocyclic orheteroaromatic ring. In a particularly interesting variant of thisembodiment R² is carbocyclic, in particular is cyclohexyl. Ininteresting alternative embodiments, R² is not hydrogen.

In one variant hereof, R² and R³ together with the intervening atomsform an optionally substituted N,O-containing heterocyclic orheteroaromatic ring.

Moreover, R⁴ is preferably selected from hydrogen, C₁₋₆-alkyl andoptionally substituted benzyl and R⁴* is hydrogen. More particular, R⁴and R⁴* are preferably both hydrogen.

In one currently particularly relevant embodiment,

X is selected from ═O and ═S;A is selected from —C(═O)— and —S(═O)₂—;

B is —O—;

D is selected from a single bond, —O—, and —NR⁹;m is an integer of 2-8 and n is 0;p is an integer of 0-2;R² is selected from hydrogen, optionally substituted C₃₋₁₂-cycloalkyl,—[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl),—(CH₂)₀₋₂-(optionally substituted aryl), —(CH₂)₀₋₂-(optionallysubstituted heteroaryl) and —(CH₂)₀₋₂-(optionally substitutedheterocyclyl);R³ is selected from optionally substituted C₃₋₁₂-cycloalkyl,—[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl), optionallysubstituted C₁₋₁₂-alkenyl, optionally substituted aryl, optionallysubstituted heterocyclyl, and optionally substituted heteroaryl;R⁴ is selected from hydrogen, optionally substituted C₃₋₁₂-cycloalkyl,—(CH₂)₀₋₂-(optionally substituted aryl), —(CH₂)₀₋₂-(optionallysubstituted heteroaryl) and —(CH₂)₀₋₂-(optionally substitutedheterocyclyl); andR⁴* is hydrogen.

In another particularly relevant embodiment,

X is selected from ═O and ═S;A is selected from —C(═O)— and —S(═O)₂—;B is selected from —(CH₂)₃₋₆— and —O—(CH₂)₂₋₅—, preferably from—(CH₂)₃₋₄— and —O—(CH₂)₁₋₃—;D is selected from a single bond, —O—, and —NR⁹;m is an integer of 2-8 and n is 0;p is an integer of 0-2;R² is selected from hydrogen, optionally substituted C₃₋₁₂-cycloalkyl,—[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl),—(CH₂)₀₋₂-(optionally substituted aryl), —(CH₂)₀₋₂-(optionallysubstituted heteroaryl) and —(CH₂)₀₋₂-(optionally substitutedheterocyclyl);R³ is selected from optionally substituted C₃₋₁₂-cycloalkyl,—[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl), optionallysubstituted C₁₋₂-alkenyl, optionally substituted aryl, optionallysubstituted heterocyclyl, and optionally substituted heteroaryl;R⁴ is selected from hydrogen, optionally substituted C₃₋₁₂-cycloalkyl,—(CH₂)₀₋₂-(optionally substituted aryl), —(CH₂)₀₋₂-(optionallysubstituted heteroaryl) and —(CH₂)₀₋₂-(optionally substitutedheterocyclyl); andR⁴* is hydrogen.

This being said, currently most interesting compounds are those selectedfrom compounds 1001-1101 described in the following:

Compound Structure 1001.

1002.

1003.

1004.

1005.

1006.

1007.

1008.

1009.

1010.

1011.

1012.

1013.

1014.

1015.

1016.

1017.

1018.

1019.

1020.

1021.

1022.

1023.

1024.

1025.

1026.

1027.

1028.

1029.

1030.

1031.

1032.

1033.

1034.

1035.

1036.

1037.

1038.

1030.

1040.

1041.

1042.

1043.

1044.

1045.

1046.

1047.

1048.

1049.

1050.

1051.

1052.

1053.

1054.

1055.

1056.

1057.

1058.

1059.

1060.

1061.

1062.

1063.

1064.

1065.

1066.

1067.

1068.

1069.

1070.

1071.

1072.

1073.

1074.

1075.

1076.

1077.

1078.

1079.

1080.

1081.

1082.

1083.

1084.

1085.

1086.

1087.

1088.

1089.

1090.

1091.

1092.

1093.

1094.

1095.

1096.

1097.

1098.

1099.

1100.

1101.

General Procedures

The compounds of the present invention can be synthesized using themethods outlined below, together with methods known in the art oforganic synthetic organic chemistry, or variations thereof asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below.

The novel compounds of formula (I) may be prepared using the reactionsand techniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and suitablefor the transformations being effected. Also, in the synthetic methodsdescribed below, it is to be understood that all proposed reactionconditions, including choice of solvent, reaction atmosphere, reactiontemperature duration of experiment and work-up procedures, are chosen tobe conditions of standard for that reaction, which should be readilyrecognized by one skilled in the art. It is understood by one skilled inthe art of organic synthesis that the functionality present on variousportions of the educt molecule must be compatible with the reagents andreactions proposed. Not all molecules of formula (I) falling into agiven class may be compatible with some of the reaction conditionsrequired in some of the methods described. Such restrictions to thesubstituents which are compatible with the reaction conditions will bereadily apparent to one skilled in the art and alternative methods canbe used.

Compounds (I) according to the present invention which are ureas (Ia)can be prepared in several ways, e.g. by reaction of amines of generalformula (II) with 1,1′-carbonyldiimidazole (CDI) or 4-nitrophenylchloroformate followed by reaction with amines of general formula (III).

Compounds (I) according to the present invention which are thioureas(Ib) can be prepared in several ways, e.g. by reaction of amines (III)with isothiocyanates of general formula (IV). Isothiocyanates (IV) areeither commercially available or can be prepared from amines of generalformula (II) by reaction with di(2-pyridyl)thionocarbonate (DPT).

Compounds (I) according to the present invention which arealkoxyguanidines (Ic) can be prepared by conversion of thioureas (Ib)into the corresponding carbodiimide (V), e.g. by reaction with acarbodiimide (e.g. EDC or DCCI) or HgO, followed by reaction withO-alkoxyhydroxylamine. In a similar manner, compounds (I) according tothe present invention which are hydroxyguanidines (Id) or guanidines(Ie) may be prepared, substituting O-alkoxyhydroxylamine withhydroxylamine or a protected hydroxylamine, or ammonia or an ammoniaequivalent, respectively. If a protected hydroxylamine or ammoniaequivalent is employed, a deprotection step is necessary. The protectinggroup may e.g. be tetrahydropyranyl (THP), t-butyl, benzyl or asilyl-based protecting group.

Alternatively, thioureas of general formula (Ib) may be methylated andsubsequently allowed to react with O-methoxyhydroxylamine, hydroxylamineor a protected hydroxylamine, or ammonia or an ammonia equivalent,respectively. If a protected hydroxylamine or ammonia equivalent isemployed, a deprotection step is necessary.

Compounds (I) according to the present invention which aremethoxyguanidines (Ic), hydroxyguanidines (Id) or guanidines (Ie) maye.g. also be prepared from N-arylsulfonyl-S-methylisothioureas,cyanamides, pyrazole-1-carboximidamides, triflate guanidines, andbenzotriazole and imidazole-containing reagents (see e.g. A. R.Katritzky et al.: J. Org. Chem. (2006) 71, 6753-6778 and referencescited herein).

Amines of general formula (III), which are hydroxamic acid esters,N-alkyl- or N-arylhydrazides, N,N′-dialkyl- or N,N′-diarylhydrazides(IIIa) can be prepared from protected amino acids of general formula(VII) (protecting group Pg e.g. Boc or phtalimido) by coupling withhydroxylamines or hydrazines of general formula (VIII) using a peptidecoupling reagent (e.g. EDC or HATU), and subsequent removal of theprotecting group.

In the special case where amines of general formula (IIIa) contain asubstituent alpha to the carbonyl group they can be prepared from aminoacids of general formula (X) or their enantiomers (obtained as describedin the literature e.g K. S. Orwig et al.: Tet. Lett. (2005) 467007-7009), followed by protection of the amino group (e.g. with Boc,phtalimido or other) and subsequent coupling with hydroxylamines orhydrazines followed by deprotection as described above.

Hydroxylamines (VIII, B═O)) are either commercially available or can beprepared from N-hydroxyphtalimide (or alternativelytert-butylhydroxycarbamate) by alkylation with a halogenide and a base(e.g. DBU) or a Mitsunobu reaction with an alcohol (using e.g. DEAD),followed by deprotection with hydrazine or methylhydrazine, resulting inhydroxylamine (VIIIa). When R² is not hydrogen, the resultinghydroxylamine (VIIIa) may be submitted to reductive amination with analdehyde or ketone followed by reduction with e.g. sodiumcyanoborohydride as described in the literature (e.g. B. J. Mavunkel etal.: Eur. J. Med. Chem. (1994) 29, 659-666; T. Ishikawa et. al.: J. Antibiotics (2000), 53 (10), 1071-1085; J. Ishwara Bhat et al.: J. Chem.Soc., Perkin Trans. 2 (2000), 1435-1446). Alternatively, alkylation ofthe hydroxylamine (VIIIa) can be achieved by a Mitsunobu reaction oralkylation after protection with e.g. 2-nitrophenylsulfonylchloride andsubsequent removal of the protecting group (using e.g. thiophenol andcesium carbonate).

Hydrazines (VIII, B═O) are either commercially available or can—in thecase where R₂ is H—be prepared from hydrazine hydrate by alkylation inthe presence of a base according to literature procedures (e.g. D. J.Drain et al.: J. Med. Chem. (1963) δ 63-9; G. B. Marini-Bettolo et al.:Rend. Ist. Super. Sanita (1960) 23 1110-27). N,N′-Disubstitutedhydrazines can be obtained from monosubstituted hydrazines (VIIIa) byreaction with an aldehyde or ketone followed by reduction with e.g.hydrogen, LiAlH₄, or borane according to literature procedures (e.g. H.Dorn et. al.: Zeitschrift für Chemie (1972) 12(4) 129-30; R. L. Hinman:JACS (1957) 79 414-417; J. A. Blair: JCS (Section) C: Organic (1970)(12) 1714-17) or alternatively by Boc-protection of hydrazine hydrate,alkylation with an alkylhalogenide in the presence of sodium hydride,followed by a second alkylation with another alkylhalogenide in thepresence of sodium hydride and finally removal of the Boc-protectinggroups (L. Ling et al.: Bioorg. Med. Chem. Lett. (2001) (11) 2715-2717).

Amines of general formula (III), which are N-alkoxy- orN-aryloxythioamides, or thiohydrazides (IIIb) can be prepared from thecorresponding carbonyl compounds (IIIa) by treatment with Lawessonreagent according to literature procedures (e.g. Thomsen et al.: Org.Synth. (1984) 62, 158, R. A. Cherkasov et al.: Tet. (1985) 41, 2567; M.P. Cava, M. J. Levinson Tet. (1985) 41, 5061).

Alternatively, protected amino acids of general formula (VII)(protecting group e.g. Boc or phtalimido) can be converted into anactivated species of general formula (XI) according to literatureprocedures (M. A: Shalaby et al.: J. Org. Chem. (1996) 61 9045-48) andsubsequently allowed to react with hydroxylamines or hydrazines ofgeneral formula (VIII) followed by deprotection to yield amines ofgeneral formula (IIIb).

Amines of general formula (III), which are N-alkoxy or N-aryloxysulfonamides, sulfonamides or sulfonylhydrazides (IIIc) can be obtainedby reaction of phtalimidoalkanesulfonylchlorides (XII) (prepared asdescribed in the literature, e.g. G. J. Atwell et al.: J. Med. Chem.(1977) 20(9) 1128-134; J. Humljan et al. i: Tet. Letters, 46 4069-4072)with hydroxylamines, amines or hydrazines (VIII), respectively, in thepresence of a base (e.g. triethyamine or N-methylmorpholine) followed bydeprotection with hydrazine hydrate. Other protecting groups thanphtalimido may be used.

Amines of general formula (III) which areN-alkoxy-P-alkylphosphonamidates or N-aryloxy-P-alkylphosphonamidates,P-alkylphosphonamidates or P-alkylphosphonohydrazidates (IIId) can beobtained by reaction of the phtalimido protected phosphonochloridates(XIII) (prepared as described in the literature, e.g. S. Gobec et al.:Tet. Lett. (2002) 43 167-170; U. Urleb et al.: Lett. In Peptide Science(1995) 2 193-197) with hydroxylamines, amines or hydrazines (VIII),respectively, in the presence of a base followed by deprotection withhydrazine hydrate. Other protecting groups than phtalimido may be used.

Amines of general formula (III) which are N-alkoxy-P-alkylphosphinicamides or N-aryloxy-P-alkylphosphinic amides, P-alkylphosphinic amidesor P-alkylphosphinic hydrazides (IIIe) can be obtained by reaction ofthe phtalimido protected alkylphosphinic chlorides (XIV) (e.g. S. Gobecet al.: Lett. In Peptide Science (1998) δ 109-114) with hydroxylamines,amines or hydrazines (VIII), respectively, in the presence of a basefollowed by deprotection with hydrazine hydrate. Other protecting groupsthan phtalimido may be employed.

Amines of general formula (III) which are sulfonylureas (IIIf) can beprepared from known literature procedures (e.g. B. Hökfelt et al.: J.Med. & Pharm. Chem. (1962) 5 231-9; R. Tull et al. JCS Section C:Organic (1967) (8) 701-2; B. Loev: J. Med. Chem. (1963) 6(5) 506-8; D.R. Cassady et al.: J. Org. Chem. (1958) 23 923-6; D. Freitag:Tetrahedron (2005) 61 5615-21; Y. Kanbe et. al.: Bioorg. Med. Chem.Lett. (2006) 16 4090-94; I. Ubarretxena-Belandia et. al.: Eur. J.Biochem. (1999) 260 794-800; B. D. Roth et al.: Bioorg. Med. Chem. Lett.(1995) 5(20) 2367-70), for instance by reaction of suitably protectedaminoalkanesulfonylchlorides (XII) with an ammonia equivalent or amine,followed by reaction with an alkyl chloroformate in the presence of abase to yield carbamates of general formula (XVI), which aresubsequently allowed to react with amines R³R⁶NH₂ to yield sulfonylureasof general formula (XVII). Alternatively, sulfonamides of generalformula (XV) can react directly with isocyanates to yield protectedsulfonylureas (XVIIa). The protecting group (e.g phtalimido, Boc orother) is subsequently removed.

Amines of general formula (III) which are N-alkoxy- or N-aryloxycarbamates or alkyl- or arylhydrazinecarboxylates (Ig) can be obtainedby reaction of protected aminoalkyl 4-nitrophenyl carbonates (XVIII)(protecting group e.g. Boc or phtalimido) with hydroxylamines orhydrazines (VIII) followed by deprotection as depicted below.

Amines of general formula (III) which are N-alkoxy- or N-aryloxy ureasor alkyl- or arylhydrazinecarboxamides (IIIh) can be prepared by methodsknown to one skilled in the art for preparing ureas. One such method isreaction of protected 4-nitrophenyl aminoalkyl carbamates (XX)(protecting group e.g. Boc or phtalimido) with hydroxylamines orhydrazines (VIII) followed by deprotection as depicted below.

As an alternative to 4-nitrophenyl aminoalkyl carbamates (XX),N-(aminoalkyl)-1H-imidazole-1-carboxamides (XXII) may be employed.

Medical Uses

The compounds of the invention is believed to be particularly useful fordown-regulating NAD via inhibition of NAMPRT, and such compounds aretherefore particularly useful for treating diseases in which activationof NF-κB is implicated. Such methods are useful in the treatment of avariety of diseases including inflammatory and tissue repair disorders;particularly rheumatoid arthritis, inflammatory bowel disease, asthmaand CPOD (chronic obstructive pulmonary disease), osteoarthritis,osteoporosis and fibrotic diseases; dermatosis, including psoriasis,atopic dermatitis and ultra-violet induced skin damage; autoimmunediseases including systemic lupus erythematosis, multiple sclerosis,psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection,Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes,glomerulonephritis, cancer, particularly wherein the cancer is selectedfrom breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder,pancreas, leukaemia, lymphoma or Hodgkin's disease, cachexia,inflammation associated with infection and certain viral infections,including Acquired Immune Deficiency Syndrome (AIDS), adult respiratorydistress syndrome, ataxia telengiectasia.

Hence, the present invention provides a compound of the formula (I) foruse as a medicament; more particular for use as a medicament for thetreatment of a disease or a condition caused by an elevated level ofnicotinamide phosphoribosyltransferase (NAMPRT), especially for thetreatment of the above-mentioned diseases and conditions.

Moreover, the invention also provides a method of inhibiting theenzymatic activity of nicotinamide phosphoribosyltransferase (NAMPRT) ina mammal, said method comprising the step of administering to saidmammal a pharmaceutically relevant amount of a compound of the generalformula (I).

Further, the invention provides a method of treating a disease orcondition (in particular the diseases and condtions mentioned above)caused by an elevated level of nicotinamide phosphoribosyltransferase(NAMPRT) in a mammal, said method comprising the step of administeringto said mammal a pharmaceutically relevant amount of a compound of thegeneral formula (I).

In such methods, the compound may be administered in combination with aDNA damaging agent.

Formulation of Pharmaceutical Compositions

The compounds of the general formula (I) are suitably formulated in apharmaceutical composition so as to suit the desirable route ofadministration.

The administration route of the compounds may be any suitable routewhich leads to a concentration in the blood or tissue corresponding to atherapeutic effective concentration.

Thus, e.g., the following administration routes may be applicablealthough the invention is not limited thereto: the oral route, theparenteral route, the cutaneous route, the nasal route, the rectalroute, the vaginal route and the ocular route. It should be clear to aperson skilled in the art that the administration route is dependent onthe particular compound in question; particularly the choice ofadministration route depends on the physico-chemical properties of thecompound together with the age and weight of the patient and on theparticular disease or condition and the severity of the same.

The compounds may be contained in any appropriate amount in apharmaceutical composition, and are generally contained in an amount ofabout 1-95%, e.g. 1-10%, by weight of the total weight of thecomposition. The composition may be presented in a dosage form which issuitable for the oral, parenteral, rectal, cutaneous, nasal, vaginaland/or ocular administration route. Thus, the composition may be in formof, e.g., tablets, capsules, pills, powders, granulates, suspensions,emulsions, solutions, gels including hydrogels, pastes, ointments,creams, plasters, drenches, delivery devices, suppositories, enemas,injectables, implants, sprays, aerosols and in other suitable form.

The pharmaceutical compositions may be formulated according toconventional pharmaceutical practice, see, e.g., “Remington'sPharmaceutical Sciences” and “Encyclopedia of PharmaceuticalTechnology”, edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker,Inc., New York, 1988. Typically, the compounds defined herein areformulated with (at least) a pharmaceutically acceptable carrier orexcipient. Pharmaceutically acceptable carriers or excipients are thoseknown by the person skilled in the art. Formation of suitable salts ofthe compounds of the Formula (I) will also be evident in view of thebefore-mentioned.

Thus, the present invention provides in a further aspect apharmaceutical composition comprising a compound of the general Formula(I) in combination with a pharmaceutically acceptable carrier.

Pharmaceutical compositions according to the present invention may beformulated to release the active compound substantially immediately uponadministration or at any substantially predetermined time or time periodafter administration. The latter type of compositions is generally knownas controlled release formulations.

In the present context, the term “controlled release formulation”embraces i) formulations which create a substantially constantconcentration of the drug within the body over an extended period oftime, ii) formulations which after a predetermined lag time create asubstantially constant concentration of the drug within the body over anextended period of time, iii) formulations which sustain drug actionduring a predetermined time period by maintaining a relatively,constant, effective drug level in the body with concomitant minimizationof undesirable side effects associated with fluctuations in the plasmalevel of the active drug substance (saw-tooth kinetic pattern), iv)formulations which attempt to localize drug action by, e.g., spatialplacement of a controlled release composition adjacent to or in thediseased tissue or organ, v) formulations which attempt to target drugaction by using carriers or chemical derivatives to deliver the drug toa particular target cell type.

Controlled release formulations may also be denoted “sustained release”,“prolonged release”, “programmed release”, “time release”,“rate-controlled” and/or “targeted release” formulations.

Controlled release pharmaceutical compositions may be presented in anysuitable dosage forms, especially in dosage forms intended for oral,parenteral, cutaneous nasal, rectal, vaginal and/or ocularadministration. Examples include single or multiple unit tablet orcapsule compositions, oil solutions, suspensions, emulsions,microcapsules, microspheres, nanoparticles, liposomes, delivery devicessuch as those intended for oral, parenteral, cutaneous, nasal, vaginalor ocular use.

Preparation of solid dosage forms for oral use, controlled release oraldosage forms, fluid liquid compositions, parenteral compositions,controlled release parenteral compositions, rectal compositions, nasalcompositions, percutaneous and topical compositions, controlled releasepercutaneous and topical compositions, and compositions foradministration to the eye will be well-known to those skilled in the artof pharmaceutical formulation. Specific formulations can be found in“Remington's Pharmaceutical Sciences”.

Capsules, tablets and pills etc. may contain for example the followingcompounds: microcrystalline cellulose, gum or gelatin as binders; starchor lactose as excipients; stearates as lubricants; various sweetening orflavouring agents. For capsules the dosage unit may contain a liquidcarrier like fatty oils. Likewise coatings of sugar or enteric agentsmay be part of the dosage unit. The pharmaceutical compositions may alsobe emulsions of the compound(s) and a lipid forming a micellularemulsion.

For parenteral, subcutaneous, intradermal or topical administration thepharmaceutical composition may include a sterile diluent, buffers,regulators of tonicity and antibacterials.

The active compound may be prepared with carriers that protect againstdegradation or immediate elimination from the body, including implantsor microcapsules with controlled release properties. For intravenousadministration the preferred carriers are physiological saline orphosphate buffered saline.

Dosages

In one embodiment, the pharmaceutical composition is in unit dosageform. In such embodiments, each unit dosage form typically comprises0.1-500 mg, such as 0.1-200 mg, e.g. 0.1-100 mg, of the compound.

More generally, the compound are preferably administered in an amount ofabout 0.1-250 mg per kg body weight per day, such as about 0.5-100 mgper kg body weight per day.

For compositions adapted for oral administration for systemic use, thedosage is normally 0.5 mg to 1 g per dose administered 1-4 times dailyfor 1 week to 12 months depending on the disease to be treated.

The dosage for oral administration of the composition in order toprevent diseases or conditions is normally 1 mg to 100 mg per kg bodyweight per day. The dosage may be administered once or twice daily for aperiod starting 1 week before the exposure to the disease until 4 weeksafter the exposure.

For compositions adapted for rectal use for preventing diseases, asomewhat higher amount of the compound is usually preferred, i.e. fromapproximately 1 mg to 100 mg per kg body weight per day.

For parenteral administration, a dose of about 0.1 mg to about 100 mgper kg body weight per day is convenient. For intravenousadministration, a dose of about 0.1 mg to about 20 mg per kg body weightper day administered for 1 day to 3 months is convenient. Forintraarticular administration, a dose of about 0.1 mg to about 50 mg perkg body weight per day is usually preferable. For parenteraladministration in general, a solution in an aqueous medium of 0.5-2% ormore of the active ingredients may be employed.

For topical administration on the skin, a dose of about 1 mg to about 5g administered 1-10 times daily for 1 week to 12 months is usuallypreferable.

Experimentals General Procedures, Preparations and Examples

For nuclear magnetic resonance ¹H NMR spectra (300 MHz) and ¹³C NMR(75.6) chemical shift values (δ) (in ppm) are quoted, unless otherwisespecified, for deuteriochloroform solutions relative totetramethylsilane (δ=0.0) or chloroform (δ=7.25) or deuteriochloroform(δ=76.81 for ¹³C NMR) standards. The value of a multiplet, eitherdefined (dublet (d), triplet (t), double dublet (dd), double triplet(dt), quartet (q)) or not (m) at the approximate mid point is givenunless a range is quoted. (bs) indicates a broad singlet.

MS was performed using an LC-MS using a Bruker Esquire 3000+ESI Iontrapwith an Agilent 1200 HPLC-system.

HPLC purifications were performed using an X-Bridge Prep C18 OBD 19×150mm column, using a gradients of Buffer A (0.1% TFA in H₂O) and Buffer B(0.1% TFA in acetonitrile).

The organic solvents used were anhydrous.

The following abbreviations have been used throughout:

CDI 1,1′-carbonyldiimidazoleDCCl dicyclohexylcarbodiimideDCM dichloromethaneDCE 1,2-dichloroethaneDIEA diisopropylehylamine

DMF N,N-dimthylformamide

DMAP N,N dimethylaminopryridineDPT di(2-pyridyl)thionocarbonateEDC N-(dimethylaminopropyl)-N-ethylcarbodiimide hydrochlorideEtOAc ethyl acetateHATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHOBt 1-hydroxybenzotriazoleMS mass spectroscopy

MM N-methylmorpholine

MR nuclear magnetic resonancert room temperatureTHF tetrahydrofuraneTLC thin layer chromatographyGeneral Procedure 1: Reaction of Amines of General Formula (II) with CDIFollowed by Reaction with Amines of General Formula (III) to Yield Ureasof General Formula (Ia).

To a solution of CDI (1.1 eq.) in THF was added amine of general formula(II) (1.0 eq.) and the mixture was stirred at rt overnight. To thereaction mixture amine of general formula (III) (1.0 eq.) was added andthe reaction was stirred at rt overnight. The solvent was evaporated invacuum and the residue was purified by chromatography(chloroform:methanol:NH₃ (25% aq.) 96:4:0.4 or with MeCN—H₂O—AcOH 3:1:1)to yield urea of general formula (Ia).

The oxalic acid salt of urea of general formula (Ia) may be obtained bydissolving compound of general formula (Ia) (1 eq.) in MeCN and adding asolution of oxalic acid (2 eq.) in MeCN.

The precipitate was filtered and dried to give the oxalic acid salt ofurea of general formula (Ia).

The HCl-salt of urea of general formula (Ia) may be obtained bydissolving compound of general formula (Ia) (1 eq) in 1N HCl/MeOH (2eq.), the solvent was evaporated, the residue was washed with DCMfollowed by Et₂O and dried to give the HCl-salt of urea of generalformula (Ia).

General Procedure 2: Reaction of Amines of General Formula (II) with4-Nitrophenyl Cholroformate Followed by Reaction with Amines of GeneralFormula (III) to Yield Ureas of General Formula (Ia).

Amine of general formula (II) (1.0 eq.) was dissolved in EtOAc, DIEA(1.2 eq.) was added, the mixture was cooled on an icebath and4-nitrophenyl chloroformate (1.1 eq.) was added with stirring. After 4 h(or consumption of the amine (II)) the reaction mixture was washedsuccessively with 5% Na2CO3 (twice), H₂O, brine, dried over Mg₂SO₄,filtered and concentrated. The resulting 4-nitrophenyl carbamate (1.0eq.) was dissolved in DMF, amine of general formula (III) (1.0 eq.) wasadded followed by HOBT (2.0 eq) and DIEA (0.5 eq.) and heated at 40° C.overnight. The mixture was concentrated and purified by chromatography(chloroform:methanol:NH3 (25% aq.) 98:2:0.2 to 96:4:0.4) to afford ureaof general formula (Ia).

The oxalic acid salt of urea of general formula (Ia) may be obtained bydissolving compound of general formula (Ia) (1 eq.) in MeCN and adding asolution of oxalic acid (2 eq.) in MeCN. The precipitate was filteredand dried to give the oxalic acid salt of urea of general formula (Ia).

General Procedure 3: Reaction of Amines of General Formula (II) with DPTFollowed by Reaction with Amines of General Formula (III) to YieldThioureas of General Formula (Ib)

Amine of general formula (II) (1.0 eq.) was dissolved in THF, thereaction mixture was cooled on an icebath and NaH (1.1 eq.) was addedwith stirring. After 2 h DPT (1.0 eq.) was added and the mixturegradually allowed to reach rt. After a further 3 h (or consumption ofthe starting materials) the resulting isothiocyanate was either purifiedby chromatography (mixtures of petroleum ether and ETOAc) or useddirectly.

To a solution in THF of the isothiocyanate (1.0 eq.) was added amine ofgeneral formula (III) (1.0 eq.) and DIEA (1.1 eq.) and the mixture wasstirred at rt overnight, concentrated and purified by chromatography(1-5% methanol in DCM) to afford thiourea of general formula (Ib).

The oxalic acid salt of thiourea of general formula (Ib) may be obtainedby dissolving compound of general formula (Ib) (1 eq.) in MeCN andadding a solution of oxalic acid (2 eq.) in MeCN. The precipitate wasfiltered and dried to give the oxalic acid salt of urea of generalformula (Ib).

General Procedure 4: Reaction of 4-Nitrophenoxycarbamates of GeneralFormula (XX) with Hydroxylamines or Hydrazines (VIII) and SubsequentDeprotection.

4-nitrophenoxycarbamate of general formula (XX) (1.0 eq.) was dissolvedin DMF, the hydroxylamine or hydrazine (2.0 eq.), HOBt (2 eq.) and DIEA(0.5 eq., or 1.5 eq. if the hydroxylamine or hydrazine is a salt) wereadded, and the mixture heated to 50 0° C. with stirring for 4 h or untilconsumption of the carbamate. The mixture was concentrated and purifiedby chromatography (1-5% MeOH in DCM). The resulting Boc-protectedcompound of general formula (XXIa) was dissolved in MeOH and 3N HCl inMeOH was added with stirring. After 2 h the mixture was concentrated andthe compound used directly as the HCl-salt or purified by chromatography(chloroform:methanol:NH₃ (25% aq.) 95:5:1) to afford compounds ofgeneral formula (IIIh).

General Procedure 5: Preparation of Amines of General Formula (IIIc) byReaction of Phtalimidoalkanesulfonylchlorides (XII) with Hydroxylamines,Amines or Hydrazines (VIII) and Subsequent Deprotection.

Phtalimidoalkanesulfonylchloride (XII) (1.0 eq.) (prepared as describedin the literature, e.g. G. J. Atwell et al.: J. Med. Chem. (1977) 20(9)1128-134; J. Humljan et al. i: Tet. Letters, 46 4069-4072) was added insmall portions to a solution of hydroxylamine, amine or hydrazine (VIII)(1.02 eq.) and triethyamine or N-methylmorpholine (1.1 eq., or 2.2 eq.if the hydroxylamine or amine is a salt) in DCM at −20° C. withstirring. The mixture was gradually allowed to reach rt, stirredovernight, concentrated. purified by chromatography (1% methanol in DCMor mixtures of petroleum ether and EtOAc) to yield phtalimido-protectedintermediates.

Deprotection: the phtalimido protected intermediate (1.0 eq.) wasdissolved in ethanol, hydrazine hydrate (2.9 eq.) was added and themixture heated in a microwave oven at 120° C. until consumption of thestarting material (typically 10-30 min). The mixture was filtered, thefilter cake washed with ethanol, the filtrate was concentrated andpurified by chromatography (chloroform:methanol:NH3 (25% aq.) 98:2:02 or90:10:1) to afford amines of general formula (IIIc).

Preparation 1: tert-butyl5-((4-nitrophenoxy)carbonylamino)pentylcarbamate (Compound 1)

tert-Butyl 5-aminopentylcarbamate (2.02 g, 10 mmol) was dissolved inEtOAc, 4-nitrophenyl carbonochloridate (2.22 g, 11 mmol) was added, themixture cooled on an icebath, DIEA (2.05 mL, 12 mmol) was added withstirring and the mixture gradually allowed to reach rt and stirred for 3h. The mixture was transferred to a separatory funnel with EtOAc andH₂O, and shaken. The organic phase was extracted with 1N HCl, H₂O, 5%NA₂CO₃, H₂O (three times), brine, dried over Mg₂SO₄, filtered andconcentrated to yield compound 9.

1H-NMR (CDCl3): δ 8.24 (m, 2H), 7.39 (m, 2H), 5.32 (bs, 1H), 4.56 (bs,1H), 3.29 (q, 2H), 3.14 (m, 2H), 1.7-1.3 (m, 6H), 1.44 (s, 9H).

Preparation 2: N-(5-aminopentyl)morpholine-2-carboxamide hydrochloride(Compound 2)

General procedure 4. Starting materials: compound 1 andtetrahydro-1,2-oxazinium (J. Chem. Soc., Pekin Trans 2 (2000),1435-144).

¹H-NMR (CD₃OD): δ 3.94 (m, 2H), 3.52 (m, 2H), 3.17 (t, 2H), 2.90 (t,2H), 1.75-1.60 (m, 6H), 1.54 (m, 2H), 1.39 (m, 2H).

Preparation 3: 3-(5-aminopentyl)-1-cyclohexyl-1-(2-morpholinoethoxy)ureadihydrochloride (Compound 3)

General procedure 4. Starting materials: compound 1 andN-cyclohexyl-O-(2-morpholinoethylhydroxylamine (see, e.g., WO2009/086835).

¹H-NMR (DMSO-d₆): δ 11.44 (bs, 1H), 7.97 (bs, 3H), 4.22 (t, 2H), 4.09(t, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.72 (m, 1H), 3.40 (m, 4H), 3.14(m, 2H), 2.77 (m, 2H), 1.8-1.0 (m, 16)

Preparation 4: 3-(5-aminopentyl)-1-isopropyl-1-(2-morpholinoethoxy)ureadihydrochloride (Compound 4)

General procedure 4. Starting materials: compound 1 andN-isopropyl-O-(2-morpholinoethylhydroxylamine (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 4.28 (t, 2H), 4.20 (m, 1H), 4.09 (m, 2H), 3.95 (m,2H), 3.56 (m, 4H), 3.26 (m, 4H), 2.95 (t, 2H), 1.71 (m, 2H), 1.63 (m,2H), 1.45 (m, 2H), 1.23 (d, 6H).

EXAMPLES Example 1N-(cyclohexylmethoxy)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1001)

General procedure 1. Starting materials: 4-aminopyridine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 3.75 (d, 2H), 3.22 (m,4H), 1.9-1.15 (m, 17H), 0.99 (m, 2H).

Example 2N-Cyclohexyl-N-(2-morpholinoethoxy)-7-(3-pyridin-4-ylureido)heptanamide(Compound 1002)

General procedure 1. Starting materials: 4-aminopyridine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

MS [M+H]⁺=476.3, [M−H]⁻=574.3.3, [M−H+HCOOH]⁻=520.5.

Example 3N-(cyclohexylmethoxy)-6-(3-pyrimidin-4-ylthioureido)hexane-1-sulfonamide(Compound 1003)

General procedure 3. Starting materials: 4-aminopyrimidine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

MS [M+H]⁺=430.2, [M−H]⁻=528.3.

Example 4N-(cyclohexylmethoxy)-6-(3-(pyridin-4-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1004)

General procedure 2. Starting materials: 4-picolylamine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): 8.47 (m, 2H), 7.36 (m, 2H), 4.39 (s, 2H), 3.75 (d, 2H),3.16 (m, 4H), 1.9-1.15 (m, 17H), 1.00 (m, 2H).

Example 5N-Cyclohexyl-N-(2-morpholinethoxy)-6-(3-pyridin-4-ylthioureido)hexane-1-sulfonamideoxalate (Compound 1005)

General procedure 3. Starting materials: 4-aminopyridine and6-amino-N-cyclohexyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (200 MHz) (DMSO-d₆): 10.99 (bs, 1H), 9.21 (t, 1H), 8.44 (d, 2H),7.88 (d, 2H), 4.11 (t, 2H), 3.74-3.60 (m, 4H), 3.58-3.39 (m, 3H), 3.42(t, 2H), 2.90 (t, 2H), 2.83-2.67 (m, 4H), 1.96-1.65 (m, 5H), 1.90-1.65(13H).

Example 6N-Cyclohexyl-N-(2-morpholinethoxy)-7-(3-pyrimidin-4-ylthioureido)heptanamide(Compound 1006)

General procedure 3. Starting materials: 4-aminopyrimidine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.79 (bs, 1H), 8.48 (m, 1H), 7.01 (m, 1H), 4.10 (m,1H), 4.08 (t, 2H), 3.71 (m, 6H), 2.67 (t, 2H), 2.56 (m, 4H), 2.51 (t,2H), 1.95-1.05 (m, 18H).

Example 7 1-(6-(morpholinosulfonyl)hexyl)-3-(pyridin-4-yl)ureahydrochloride (compound 1007)

General procedure 1. Starting materials: 4-aminopyridine and6-(morpholinosulfonyl)hexane-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (200 MHz) (DMSO-d₆): δ 14.36 (bs, 1H), 10.85 (bs, 1H), 8.51 (d,2H), 7.84 (d, 2H), 7.22 (bs, 1H), 4.03 (t, 2H), 3.02-3.44 (m, 6H),1.90-1.54 (m, 6H), 1.54-1.21 (m, 6H).

Example 8N-Cyclohexyl-N-(2-morpholinethoxy)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamideoxalate (Compound 1008)

General procedure 1. Starting materials: 4-aminopyridine and6-amino-N-cyclohexyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (200 MHz) (DMSO-d₆): 10.25-9.50 (bs, 1H), 8.36 bs, 2H), 7.56 (bs,2H), 7.23-6.78 (m, 1H), 4.40-3.92 (m, 6H), 3.40-3.70 (m, 3H), 3.35-2.97(m, 4H), 2.80-2.59 (m, 4H), 2.00-1.64 (m, 5H), 1.64-0.91 (m, 13H).

Example 9N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-(pyridin-3-ylmethyl)ureido)heptanamide(Compound 1009)

General procedure 2. Starting materials: 3-picolylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.50 (d, 1H), 8.43 (dd, 1H), 7.80 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.14 (bs, 1H), 4.08 (t, 2H), 3.72 (m, 4H), 3.15 (t,2H), 2.68 (t, 2H), 2.56 (m, 4H), 2.49 (t, 2H), 1.95-1.1 (18H).

Example 10N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-(pyridin-4-ylmethyl)ureido)heptanamide(Compound 1010)

General procedure 2. Starting materials: 4-picolylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD)): δ 8.47 (m, 2H), 7.36 (m, mH), 4.379 (s, 2H), 4.14 (bs,1H), 4.08 (t, 2H), 3.72 (m, 4H), 3.16 (t, 2H), 2.67 (t, 2H), 2.56 (m,4H), 2.50 (t, 2H), 1.95-1.05 (18H).

Example 116-(3-1,2,4-triazin-3-ylthioureido)-N-(cyclohexylmethoxy)hexane-1-sulfonamide(Compound 1011)

General procedure 3. Starting materials: 1,2,4-triazin-3-amine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (DMSO-d₆): δ 11.12 (bs, 1H), 10.96 (t, 1H), 9.97 (bs, 1H), 9.08(d, 1H), 8.72 (d, 1H), 3.65 (m, 4H), 3.12 (m, 2H), 1.65 (m, 10H), 1.41(m, 4H), 1.16 (m, 3H), 0.90 (m, 2H).

Example 127-(3-1,2,4-triazin-3-ylthioureido)-N-cyclohexyl)-N-(2-morpholinoethoxy)heptanamide(Compound 1012)

General procedure 3. Starting materials: 1,2,4-triazin-3-amine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.98 (d, 2H), 8.63 (d, 2H), 4.14 (bs, 1H), 3.76 (t,2), 3.72 (m, 4H), 2.68 (t, 2H), 2.57 (m, 4H), 2.51 (m, 2H), 1.9-1.25 (m,17H), 1.20 (m, 1H).

Example 13N-(cyclohexylmethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1013)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(cyclohexylmethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethy)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹³C-NMR (CD₃OD): δ 160.99, 148.94, 148.38, 137.47, 125.26, 83.80, 73.00,71.59, 71.42, 71.38, 68.74, 59.14, 53.53, 46.11, 42.18, 40.92, 38.37,31.04, 29.29, 27.56, 27.39, 26.88, 23.53.

Example 14N-(cyclohexylmethoxy)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1014)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (bs, 1H), 8.43 (d, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.75 (d, 2H), 3.16 (m, 4H), 1.85-1.1 (m, 17), 1.00(m, 2H).

Example 15N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-(pyridin-3-ylmethyl)thioureido)heptanamide(Compound 1015)

General procedure 3. Starting materials: 3-picolylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.52 (bs, 1H), 8.43 (d, 1H), 7.85 (m, 1H), 7.42 (m,1H), 4.82 (s, 2H), 4.13 (bs, 1H), 4.08 (t, 2H), 3.72 (m, 4H), 3.46 (m,2H), 2.68 (m, 2H), 2.56 (m, 4H), 2.49 (t, 2H), 1.95-1.1 (m, 18H).

Example 16N-(cyclohexylmethoxy)-6-(3-(3,5-dimethylisoxazol-4-yl)thioureido)hexane-1-sulfonamide(Compound 1016)

General procedure 3. Starting materials: 3,5-dimethylisoxazol-4-amineand 6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (DMSO-d₆): δ 9.96 (s, 1H), 8.67 (bs, 1H), 7.74 (bs, 1H), 3.66 (d,2H), 3.42 (m, 2H), 3.11 (m, 2H), 2.21 (s, 3H), 2.06 (s, 3H), 1.80-0.8(m, 19).

Example 17N-Cyclohexyl-7-(3-(3,5-dimethylisoxazol-4-yl)thioureido)-N-(2-morpholinoethoxy)heptanamide(Compound 1017)

General procedure 3. Starting materials: 3,5-dimethylisoxazol-4-amineand 7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g.,WO 2009/086835).

¹H-NMR (DMSO-d₆): δ 8.65 (bs, 1H), 7.73 (bs, 1H), 4.03 (bs, 1H), 3.95(t, 2H), 3.57 (m, 4H), 3.40 (m, 2H), 2.53 (m, 2H), 2.43 (m, 4H), 2.39(t, 2H), 2.21 (s, 3H), 2.05 (s, 3H), 1.8-1.1 (m, 18H).

Example 18 1-(6-morpholinosulfonyl)hexyl)-3-(pyridin-3-ylmethyl)ureahydrochloride (Compound 1018)

General procedure 1. Starting materials: 3-picolylamine and6-(morpholinosulfonyl)hexane-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (400 MHz) (DMSO-d₆): δ 8.75-8.67 (m, 2H), 8.27 (m, 1H), 7.88 (m,1H), 6.59 (bs, 1H), 6.22 (bs, 1H), 4.34 (s, 2H), 4.03 (t, 2H), 3.27 (m,2H), 3.18 (m, 2H), 2.98 (t, 2H), 1.79 (m, 2H), 1.69 (m, 2H), 1.61 (m,2H), 1.44-1.31 (m, 4H), 1.20-1.31 (m, 2H).

Example 19N-(cyclohexylmethoxy)-6-(3-pyrazin-2-ylthioureido)hexane-1-sulfonamide(Compound 1019)

General procedure 3. Starting materials: pyrazin-2-amine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.38 (d, 1H), 8.24 (m, 1H), 8.19 (d, 1H), 3.74 (m,4H), 3.20 (m, 2H), 1.9-1.4 (m, 13), 1.26 (m, 4H), 0.99 (m, 2H).

Example 20N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-(2-pyridin-3-yl)ethyl)ureido)heptanamide(Compound 1020)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.42 (d, 1H), 8.40 (dd, 1H), 7.75 (dt, 1H), 7.39 (m,1H), 4.15 (bs, 1H), 4.08 (t, 2H), 3.72 (m, 4H), 3.39 (t, 2H), 3.10 (t,2H), 2.83 (t, 2H), 2.67 (m, 2H), 2.56 (m, 4H), 2.49 (t, 2H), 1.95-1.05(m, 18H).

Example 21N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-(2-pyridin-4-yl)ethyl)ureido)heptanamide(Compound 1021)

General procedure 2. Starting materials: 2-(pyridin-4-yl)ethanamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.44 (m, 2H), 7.33 (m, 2H), 4.15 (bs, 1H), 4.08 (t,2H), 3.72 (m, 4H), 3.42 (t, 2H), 3.10 (t, 2H), 2.85 (t, 2H), 2.67 (m,2H), 2.56 (m, 4H), 2.49 (t, 2H), 1.95-1.25 (m, 17H), 1.10 (m, 1H).

Example 22N-Isopropyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1022)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-isopropyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.18 (t, 2H), 3.98 (m, 1H), 3.71 (m, 4H), 3.22 (m,2H), 3.16 (t, 2H), 2.66 (m, 2H), 2.55 (m, 4H), 1.87 (m, 2H), 1.51 (m,4H), 1.41 (m, 2H), 1.29 (d, 6H).

Example 23N-(5-(3-(pyridin-3-ylmethyl)ureido)pentyl)morpholine-2-carboxamide(Compound 1023)

General procedure 2. Starting materials: 3-picolylamine and compound 2.

¹H-NMR (CD₃OD): δ 8.50 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 6.98 (t, 1H), 4.37 (s, 2H), 3.97 (m, 2H), 3.55 (m, 2H), 3.16 (m,4H), 1.73 (m, 4H), 1.53 (m, 4H), 1.37 (m, 2H).

Example 24 N-(5-(3-pyridin-4-ylureido)pentyl)morpholine-2-carboxamide(Compound 1024)

General procedure 1. Starting materials 4-aminopyridine and compound 2.

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.47 (m, 2H), 3.96 (t, 2H), 3.55 (t,2H), 3.22 (m, 4H), 1.72 (m, 4H), 1.57 (m, 4H), (m, 2H).

Example 25N-Cyclohexyl-N-(3-morpholinopropyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1025)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclohexyl-N-(3-morholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.50 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 3.71 (m, 4H), 3.52 (m, 1H), 3.24 (m, 2H), 3.15 (t,2H), 3.02 (m, 2H), 2.49 (m, 4H), 2.40 (t, 2H), 1.9-1.25 (m, 19H), 1.18(m, 1H).

Example 26N-Cyclohexyl-N-(3-morpholinopropyl)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1026)

General procedure 1. Starting materials: 4-aminopyridine and6-amino-N-cyclohexyl-N-(3-morholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 3.70 (m, 4H), 3.51 (m,1H), 3.23 (m, 4H), 3.03 (m, 2H), 2.47 (m, 4H), 2.37 (t, 2H), 1.82 (m,8H), 1.7-1.25 (m, 11H), 1.17 (m, 1H).

Example 27N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-pyrazin-2-ylthioureido)heptanamide(Compound 10127)

General procedure 3. Starting materials: pyrazin-2-amine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.38 (d, 1H), 8.23 (dd, 1H), 8.20 (d, 1H), 4.14 (bs,1H), 4.07 (t, 2H), 3.71 (m, 6H), 2.67 (t, 2H), 2.55 (m, 4H), 2.51 (t,2H), 1.9-1.25 (m, 17H), 1.20 (m, 1H).

Example 28N-(cyclohexylmethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-6-(3-(pyridin-3-ylmethyl)thioureido)hexane-1-sulfonamide(Compound 1028)

General procedure 3. Starting materials: 3-picolylamine and6-amino-N-(cyclohexylmethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethy)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.53 (d, 1H), 8.44 (dd, 1H), 7.85 (dt, 1H), 7.42 (m,1H), 4.82 (s, 2H), 3.87 (d, 2H), 3.72 (t, 2H), 3.66 (m, 6H), 3.6-3.4 (m,6H), 3.37 (s, 3H), 3.18 (m, 2H), 1.87 (m, 2H), 1.85-1.15 (m, 15H), 1.05(m, 2H).

Example 29N-(cyclohexylmethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1029)

General procedure 1. Starting materials: 4-amiopyridine and6-amino-N-(cyclohexylmethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 3.87 (d, 2H), 3.72 (t,2H),), 3.66 (m, 6H), 3.55 (m, 2H), 3.44 (t, 2H), 3.37 (s, 3H), 3.21 (m,4H), 1.89 (m, 2H), 1.8-1.1 (m, 15H), 1.04 (m, 2H).

Example 30N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1030)

General procedure 1. Starting materials: 4-aminopyridine and6-amino-N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 3.89 (d, 2H), 3.71 (m,4H), 3.42 (t, 2H), 3.22 (m, 4H), 2.67 (t, 2H), 2.53 (m, 4H), 1.95-1.15(m, 17), 1.05 (m, 2H).

Example 31N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1031)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.90 (d, 2H), 3.71 (m, 4H), 3.42 (t, 2H), 3.16 (m,4H), 2.68 (t, 2H), 2.54 (m, 4H), 1.87 (m, 2H), 1.83-1.58 (m, 6H), 1.52(m, 4H), 1.39 (m, 2H), 1.26 (m, 3H), 1.06 (m, 2H).

Example 32N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)-6-(3-(2-(pyridin-3-yl)ethyl)ureido)hexane-1-sulfonamide(Compound 1032)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine and6-amino-N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.42 (d, 1H), 8.40 (dd, 1H), 7.75 (dt, 1H), 7.39 (m,1H), 3.90 (d, 2H), 3.71 (m, 4H), 3.39 (m, 4H), 3.19 (m, 2H), 3.11 (t,2H), 2.84 (t, 2H), 2.68 (t, 2H), 2.53 (m, 4H), 1.87 (m, 2H), 1.85-1.1(m, 15H), 1.05 (m, 2H).

Example 33N-(cyclohexylmethoxy)-6-(3-(2-(pyridin-3-yl)ethyl)ureido)hexane-1-sulfonamide(Compound 1033)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine and6-amino-N-(cyclohexylmethoxy)hexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.41 (m, 2H), 7.75 (m, 1H), 7.39 (m, 1H), 3.75 (d,2H), 3.39 (t, 2H), 3.18 (m, 2H), 3.10 (t, 2H), 2.84 (t, 2H), 1.85-1.1(m, 17H), 1.0 (m, 2H).

Example 34N-cyclohexyl-N-(2-morpholinoethoxy)-5-(3-pyridin-4-ylureido)pentane-1-sulfonamide(Compound 1034)

General procedure 1. Starting materials: 4-aminopyridine and5-amino-N-cyclohexyl-N-(2-morpholinoethoxy)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 4.16 (m, 2H), 3.70 (m,4H), 3.56 (m, 1H), 3.24 (m, 4H), 2.64 (t, 2H), 2.54 (m, 4H), 2.00-1.05(m, 16H).

Example 35N-cyclohexyl-N-(2-morpholinoethoxy)-7-(3-pyridin-4-ylureido)heptane-1-sulfonamide(Compound 1035)

General procedure 1. Starting materials: 4-aminopyridine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 4.16 (m, 2H), 3.71 (m,4H), 3.58 (m, 1H), 3.19 (m, 4H), 2.65 (t, 2H), 2.55 (m, 4H), 2.00-1.05(m, 20H).

Example 36N-(cyclohexylmethoxy)-6-(3-pyrimidin-4-ylureido)hexane-1-sulfonamide(Compound 1036)

Compound 1003 (225 mg, 0.52 mmol) was dissolved in DCM, EDC (301 mg,1.56 mmol) was added and the mixture heated with stirring at 45° C.overnight. A little water was added, the mixture was concentrated andthe residue was purified by chromatography (1-5% methanol in DCM) toyield compound 1036.

¹H-NMR (CDCl₃): δ 9.55 (bs, 1H), 9.04 (t, 1H), 8.75 (m, 1H), 8.42 (d,1H), 7.76 (s, 1H), 6.89 (m, 1H), 3.79 (d, 2H), 3.38 (m, 2H), 3.20 (m,2H), 1.83 (m, 2H), 1.75-1.05 (m, 15H), 0.93 (m, 2H).

Example 371-cyclohexyl-1-(2-morphlinethoxy)-3-(5-(3-(pyridin-3-ylmethyl)ureido)pentyl)urea(Compound 1037)

General procedure 2. Starting materials: 3-picolylamine and compound 3.

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.98 (t, 2H), 3.82 (m, 1H), 3.76 (m, 4H), 3.22 (t,2H), 3.14 (t, 2H), 2.83 (t, 2H), 2.77 (m, 4H), 1.9-1.45 (m, 1H), 1.36(m, 4H), 1.15 (m, 1H).

Example 381-cyclohexyl-1-(2-morpholinethoxy)-3-(5-(3-(2-(pyridin-3-yl)ethyl)ureido)pentyl)urea(Compound 1038)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine andcompound 3.

¹H-NMR (CD₃OD): δ 8.42 (d, 1H), 8.40 (dd, 1H), 7.76 (dt, 1H), 7.40 (m,1H), 3.96 (t, 2H), 3.85 (m, 1H), 3.74 (m, 4H), 3.39 (t, 2H), 3.23 (t,2H), 3.10 (t, 2H), 2.84 (t, 2H), 2.62 (t, 2H), 2.58 (m, 4H), 1.9-1.05(m, 16).

Example 39N-Cyclohexyl-N-(2-morpholinethoxy)-7-(3-pyrimidin-4-ylureido)heptanamide(Compound 1039)

Compound 1006 (39 mg, 0.08 mmol) was dissolved in DCM, EDC (46 mg, 0.24mmol) was added and the mixture heated with stirring at 45° C.overnight. A little water was added, the mixture was concentrated andthe residue was purified by chromatography (1-5% methanol in DCM) toyield compound 1039.

¹H-NMR (CD₃OD): δ 8.73 (bs, 1H), 8.43 (d, 1H), 7.30 (m, 1H), 4.30 (m,1H), 4.08 (m, 2H), 3.71 (m, 6H), 2.67 (t, 2H), 2.56 (m, 4H), 2.50 (t,2H), 1.95-0.75 (m, 18H).

Example 40N-(Cyclohexylmethoxy)-N-(2-morpholmethyl)-6-(3-(2-(pyridin-2-yl)ethyl)ureido)hexane-1-sulfonamide(Compound 1040)

General procedure 2. Starting materials: 2-(pyridin-2-yl)ethanamine and6-amino-N-(cyclohexylmethoxy)-N-(2-morpholinoethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.48 (dd, 1H), 7.78 (dt, 1H), 7.35 (d, 1H), 7.28 (m,1H), 3.90 (d, 2H), 3.71 (m, 4H), 3.49 (t, 2H), 3.42 (t, 2H), 3.19 (m,2H), 3.11 (t, 2H), 2.96 (t, 2H), 2.68 (t, 2H), 2.53 (m, 4H), 1.95-1.1(m, 17), 1.05 (m, 2H).

Example 41N-Cyclohexyl-N-(2-morpholinethoxy)-7-(3-(2-(pyridin-2-yl)ethyl)ureido)heptanamide(Compound 1041)

General procedure 2. Starting materials: 2-(pyridin-2-yl)ethanamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.48 (dd, 1H), 7.78 (dt, 1H), 7.35 (d, 1H), 7.28 (m,1H), 4.15 (m, 1H), 4.08 (t, 2H), 3.72 (m, 4H), 3.49 (t, 2H), 3.10 (t,2H), 2.96 (t, 2H), 2.67 (t, 2H), 2.56 (m, 4H), 2.49 (m, 2H), 1.95-1.05(m, 18H).

Example 42N-Cyclohexyl-N-(2-morpholinethoxy)-5-(3-(pyridin-3-yl)methyl)ureido)pentane-1-sulfonamide(Compound 1042)

General procedure 2. Starting materials: 3-picolylamine and5-amino-N-cyclohexyl-N-(2-morpholinoethoxy)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.80 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.16 (t, 2H), 3.71 (m, 4H), 3.59 (m, 1H), 3.19 (m,4H), 2.65 (t, 2H), 2.55 (m, 4H), 1.90 (m, 6H), 1.75-1.25 (m, 9), 1.19(m, 1H).

Example 43N-Cyclohexyl-N-(2-morpholinethoxy)-7-(3-(pyridin-3-yl)methyl)ureido)heptane-1-sulfonamide(Compound 1043)

General procedure 2. Starting materials: 3-picolylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.80 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.16 (t, 2H), 3.71 (m, 4H), 3.58 (m, 1H), 3.17 (m,4H), 2.65 (t, 2H), 2.55 (m, 4H), 2.0-1.1 (m, 20H).

Example 441-Isopropyl-1-(2-morpholinethoxy)-3-(5-(3-(pyridin-3-ylmethyl)ureido)pentyl)urea(Compound 1044)

General procedure 2. Starting materials: 3-picolylamine and compound 4.

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.22 (m, 1H), 3.99 (t, 2H), 3.72 (m, 4H), 3.22 (t,2H), 3.13 (t, 2H), 2.63 (t, 2H), 2.58 (m, 4H), 1.52 (m, 4), 1.38 (m,2H), 1.18 (d, 6H).

Example 451-Isopropyl-1-(2-morpholinethoxy)-3-(5-(3-(pyridin-3-ylethyl)ureido)pentyl)urea(Compound 1045)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine andcompound 4.

¹H-NMR (CD₃OD): δ 8.41 (m, 2H), 7.77 (dt, 1H), 7.40 (m, 1H), 4.25 (m,1H), 3.98 (t, 2H), 3.74 (m, 4H), 3.39 (t, 2H), 3.23 (t, 2H), 3.10 (t,2H), 2.83 (t, 2H), 2.63 (t, 2H), 2.57 (m, 4H), 1.53 (m, 4), 1.36 (m,2H), 1.17 (d, 6H).

Example 461-Isopropyl-1-(2-morpholinethoxy)-3-(5-(3-(pyridin-4-yl)ureido)pentyl)urea(Compound 1046)

General procedure 1. Starting materials: 4-pyridylamine and compound 4.

¹H-NMR (CD₃OD): δ 8.29 (m, 2H), 7.46 (m, 2H), 4.25 (m, 1H), 3.97 (t,2H), 3.73 (m, 4H), 3.24 (m, 4H), 2.60 (t, 2H), 2.55 (m, 4H), 1.60 (m,4), 1.42 (m, 2H), 1.16 (d, 6H).

Example 47N-Isopropyl-N-(3-morpholinopropyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1047)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-isopropyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.22 (m, 1H), 3.99 (t, 2H), 3.72 (m, 4H), 3.22 (t,2H), 3.13 (t, 2H), 2.63 (t, 2H), 2.58 (m, 4H), 1.52 (m, 4H), 1.38 (m,2H), 1.18 (d, 6H).

Example 48N-Isopropyl-N-(3-morpholinopropyl)-6-(3-(2-(pyridin-3-yl)ethyl)ureido)hexane-1-sulfonamide(Compound 1048)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine and6-amino-N-isopropyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.41 (m, 2H), 7.75 (dt, 1H), 7.40 (m, 1H), 3.99 (m,1H), 3.70 (m, 4H), 3.39 (t, 2H), 3.21 (t, 2H), 3.10 (t, 2H), 3.02 (m,2H), 2.84 (t, 2H), 2.47 (m, 4H), 2.39 (t, 2H), 1.82 (m, 4H), 1.47 (m,4H), 1.37 (m, 2H), 1.25 (d, 6H).

Example 49N-Isopropyl-N-(3-morpholinopropyl)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1049)

General procedure 1. Starting materials: 4-pyridylamine and6-amino-N-isopropyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 3.99 (m, 1H), 3.71 (m,4H), 3.22 (m, 4H), 3.02 (m, 2H), 2.47 (m, 4H), 2.39 (t, 2H), 1.82 (m,4H), 1.49 (m, 6H), 1.25 (d, 6H).

Example 50N-Cyclopentyl-N-(3-morpholinopropyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1050)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclopentyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.07 (m, 1H), 3.70 (m, 4H), 3.17 (m, 4H), 3.03 (m,2H), 2.48 (m, 4H), 2.39 (t, 2H), 1.95-1.30 (m, 18H).

Example 51N-(Cyclohexylmethoxy)-5-(3-(pyridin-3-ylmethyl)ureido)pentane-1-sulfonamide(Compound 1051)

General procedure 2. Starting materials: 3-picolylamine and5-amino-N-(cyclohexylmethoxy)pentane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.75 (d, 2H), 3.17 (m, 4H), 1.75 (m, 8H), 1.51 (m,4H), 1.26 (m, 3H), 0.99 (m, 2H).

Example 521-(5-(morpholinosulfonyl)pentyl)-3-(3-(pyridin-3-ylmethyl)urea (compound1052)

General procedure 2. Starting materials: 3-picolylamine and5-(morholinosulfonyl)pentane-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.10 (t, 2H), 3.36 (t, 2H), 3.19 (m, 4H), 1.87 (m,4H), 1.71 (m, 2H), 1.51 (m, 4H).

Example 53N-(Cyclohexylmethoxy)-7-(3-(pyridin-3-ylmethyl)ureido)heptane-1-sulfonamide(Compound 1053)

General procedure 2. Starting materials: 3-picolylamine and7-amino-N-(cyclohexylmethoxy)heptane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.75 (d, 2H), 3.16 (m, 4H), 1.76 (m, 8H), 1.6-1.1 (m,11H), 0.99 (m, 2H).

Example 541-(7-(morpholinosulfonyl)heptyl)-3-(3-(pyridin-3-ylmethyl)urea (compound1054)

General procedure 2. Starting materials: 3-picolylamine and7-(morholinosulfonyl)heptane-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.11 (t, 2H), 3.36 (t, 2H), 3.17 (m, 4H), 1.86 (m,4H), 1.71 (m, 2H), 1.49 (m, 4H), 1.37 (m, 4H).

Example 55N-Cyclohexyl-N-(2-morpholinoethoxy)-7-(3-(pyridin-2-ylmethyl)ureido)heptanamide(Compound 1055)

General procedure 2. Starting materials: 2-picolylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.48 (d, 1H), 7.82 (t, 1H), 7.42 (d, 1H), 7.30 (m,1H), 4.44 (s, 2H), 4.17 (m, 1H), 4.10 (t, 2H), 3.73 (m, 4H), 3.16 (t,2H), 2.8-2.4 (m, 8H), 1.9-1.25 (m, 17H), 1.21 (m, 1H).

Example 56N-Cyclopentyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1056)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclopentyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.20 (bs, 2H), 4.04 (m, 1H), 3.70 (t, 4H), 3.21 (bs,2H), 3.16 (t, 2H), 2.65 (t, 2H), 2.54 (t, 4H), 2.0-1.3 (m, 16H).

Example 57N-Cycloheptyl-N-(3-morpholinopropyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1057)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cycloheptyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 3.71 (m, 4H), 3.65 (m, 1H), 3.23 (m, 2H), 3.15 (t,2H), 3.01 (m, 2H), 2.47 (m, 4H), 2.38 (t, 4H), 2.0-1.3 (m, 22H).

Example 58N-Cycloheptyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1058)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cycloheptyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

MS [M+H]⁺=540.3, [M−H+ HCOOH]⁻=584.5.

Example 59N-Cyclobutyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1059)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclobutyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.24 (m, 1H), 4.20 (m, 2H), 3.71 (t, 4H), 3.15 (t,2H), 3.07 (t, 2H), 2.70 (t, 2H), 2.57 (t, 4H), 2.41 (m, 2H), 2.15 (m,2H), 1.84 (m, 2H), 1.74 (m, 2H), 1.50 (m, 4H), 1.39 (m, 2H).

Example 60N-Cyclobutyl-N-(3-morpholinopropyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1060)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclobutyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.21 (m, 1H), 3.71 (m, 4H), 3.29 (m, 2H), 3.15 (t,2H), 2.97 (m, 2H), 2.48 (m, 4H), 2.41 (t, 2H), 2.21 (m, 4H), 1.74 (m,6H), 1.43 (m, 6H).

Example 61N-Cyclohexyl-N-(3-(dimethylamino)propyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1061)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclohexyl-N-(3-dimethylamino)propyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 3.51 (m, 1H), 3.17 (m, 4H), 3.02 (m, 2H), 2.35 (t,2H), 2.26 (s, 6H), 1.9-1.25 (m, 19H), 1.18 (m, 1H).

Example 62N-Cyclohexyl-N-(2-morpholinoethoxy)-7-(3-pyridin-3-ylthioureido)heptanamide(Compound 1062)

General procedure 3. Starting materials: 3-pyridylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.59 (d, 1H), 8.30 (d, 1H), 8.04 (bd, 1H), 7.42 (m,1H), 4.15 (m, 1H), 4.10 (t, 2H), 3.73 (m, 4H), 3.60 (m, 2H), 2.8-2.4 (m,8H), 1.9-1.25 (m, 17H), 1.20 (m, 1H).

Example 63N-Cyclohexyl-N-(2-morpholinoethyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1063)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclohexyl-N-(2-morpholinoethyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 3.70 (m, 4H), 3.51 (m, 1H), 3.34 (t, 2H), 3.14 (m,4H), 2.54 (m, 6H), 1.9-1.25 (m, 17H), 1.18 (m, 1H).

Example 64N-Cyclopentyl-N-(3-morpholinopropyl)-6-(3-pyridin-4-ylthioureido)hexane-1-sulfonamide(Compound 1064)

General procedure 3. Starting materials: 4-pyridylamine and6-amino-N-cyclopentyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.35 (m, 2H), 7.74 (m, 2H), 4.07 (m, 1H), 3.70 (m,4H), 3.62 (t, 2H), 3.18 (m, 2H), 3.05 (m, 2H), 2.47 (m, 4H), 2.38 (t,2H), 1.95-1.35 (m, 18H).

Example 65N-Cyclohexyl-N-(2-morpholinoethoxy)-7-(3-pyridin-3-ylureido)heptanamide(Compound 1065)

General procedure 1. Starting materials: 3-pyridylamine and7-amino-N-cyclohexyl-N-(2-morpholinoethoxy)heptanamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.55 (d, 1H), 8.14 (dd, 1H), 7.96 (dt, 1H), 7.35 (m,1H), 4.15 (m, 1H), 4.09 (t, 2H), 3.72 (t, 4H), 3.23 (t, 2H), 2.67 (t,2H), 2.56 (t, 4H), 2.51 (t, 2H), 1.9-1.1 (m, 18H).

Example 66N-Cyclopentyl-N-(3-morpholinopropyl)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1066)

General procedure 1. Starting materials: 4-pyridylamine and6-amino-N-cyclopentyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.28 (m, 2H), 7.46 (m, 2H), 4.07 (m, 1H), 3.70 (m,4H), 3.23 (t, 2H), 3.18 (m, 2H), 3.04 (m, 2H), 2.47 (m, 4H), 2.38 (t,2H), 1.95-1.15 (m, 18H).

Example 67 EthylN-cyclohexyl-P-(6-(3-pyridin-3-ylmethyl)ureido)phosphonamidate (Compound1067)

General procedure 2. Starting materials: 3-picolylamine and ethylP-aminohexyl-N-cyclohexylphosphonamidate (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.99 (m, 2H), 3.14 (t, 2H), 2.97 (m, 1H), 1.89 (m,2H), 1.8-1.05 (m, 21H).

Example 681-(6-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)hexyl)-3-(pyridin-3-ylmethyl)urea(Compound 1068)

General procedure 2. Starting materials: 3-picolylamine and6-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)hexan-1-amine (see, e.g., WO2009/086835).

¹H-NMR (DMSO-d₆): δ 8.45 (d, 1H), 8.42 (dd, 1H), 7.63 (dt, 1H), 7.33 (m,1H), 7.17 (m, 4H), 6.37 (t, 1H), 5.98 (t, 1H), 4.39 (s, 2H), 4.19 (d,2H), 3.47 (t, 2H), 3.09 (m, 2H), 2.97 (m, 2H), 2.87 (t, 2H), 1.64 (m,2H), 1.34 (m, 4H), 1.25 (m, 2H).

Example 69N-cyclopentyl-N-(3-morpholinopropyl)-5-(3-(pyridin-3-ylmethyl)ureido)pentane-1-sulfonamide(Compound 1069)

General procedure 2. Starting materials: 3-picolylamine and5-amino-N-cyclopentyl-N-(3-morpholinopropyl)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.07 (m, 1H), 3.70 (m, 4H), 3.17 (m, 4H), 3.03 (m,2H), 2.47 (m, 4H), 2.38 (t, 2H), 1.95-1.40 (m, 16H).

Example 70N-cyclobutyl-N-(3-morpholinopropyl)-5-(3-(pyridin-3-ylmethyl)ureido)pentane-1-sulfonamide(Compound 1070)

General procedure 2. Starting materials: 3-picolylamine and5-amino-N-cyclobutyl-N-(3-morpholinopropyl)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.21 (m, 1H), 3.71 (t, 4H), 3.29 (m, 2H), 3.15 (t,2H), 2.97 (m, 2H), 2.48 (t, 4H), 2.41 (t, 2H), 2.20 (m, 4H), 1.9-1.35(m, 10H).

Example 71N-cyclobutyl-N-(2-morpholinoethoxy)-5-(3-(pyridin-3-ylmethyl)ureido)pentane-1-sulfonamide(Compound 1071)

General procedure 2. Starting materials: 3-picolylamine and5-amino-N-cyclobutyl-N-(2-morpholinoetoxy)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.25 (m, 1H), 4.20 (m, 2H), 3.72 (t, 4H), 3.16 (t,2H), 3.07 (t, 2H), 2.70 (t, 2H), 2.57 (t, 4H), 2.41 (m, 2H), 2.15 (m,2H), 2.87 (m, 2H), 1.75 (m, 2H), 1.52 (m, 4H).

Example 72 Ethylmorpholino(6-(3-pyridin-3-ylmethyl)ureido)hexyl)phosphinate (compound1072)

General procedure 2. Starting materials: 3-picolylamine and ethyl6-aminohexyl(morpholino)phosphinate (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.10 (m, 2H), 3.97 (t, 2H), 3.37 (m, 2H), 3.15 (t,2H), 1.95-1.25 (m, 17H).

Example 731-(6-(4-acetylpiperazin-1-ylsulfonyl)hexyl)-3-(pyridin-3-ylmethyl)urea(Compound 1073)

General procedure 2. Starting materials: 3-picolylamine and1-(4-(6-aminohexylsulfonyl)piperazin-1-yl)ethanone (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 3.64 (m, 4H), 3.32 (m, 2H), 3.26 (t, 2H), 3.15 (t,2H), 3.04 (m, 2H), 2.14 (s, 3H), 1.79 (m, 2H), 1.89 (m, 4H), 1.39 (m,2H)

Example 74N-Cyclopentyl-N-(2-morpholinoethoxy)-5-(3-(pyridin-3-ylmethyl)ureido)pentane-1-sulfonamide(Compound 1074)

General procedure 2. Starting materials: 3-picolylamine and5-amino-N-cyclopentyl-N-(2-morpholinoetoxy)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.80 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.20 (bs, 2H), 4.04 (m, 1H), 3.70 (t, 4H), 3.17 (m,4H), 2.65 (t, 2H), 2.54 (t, 4H), 2.0-1.45 (m, 14H).

Example 75N-Cyclohexyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamideoxalate (Compound 1075)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-cyclohexyl-N-(2-morpholinoetoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (400 MHz, DMSO-d₆): δ 8.46 (d, 1H), 8.43 (dd, 1H), 7.63 (dt, 1H),7.33 (m, 1H), 6.36 (t, 1H), 5.99 (t, 1H), 4.21 (d, 2H), 4.09 (t, 2H),3.69-3.61 (m, 4H), 3.50 (m, 1H), 3.22 (t, 2H), 2.99 (m, 2H), 2.88-2.78(m, 2H), 2.76-2.64 (m, 4H), 1.92-1.81 (m, 2H), 1.80-1.65 (m, 4H),1.63-1.32 (m, 7H), 1.32-1.19 (m, 4H), 1.16-1.00 (m, 1H).

Example 76 N-Phenyl-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(compound 1076)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-phenylhexane-1-sulfonamide (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.48 (d, 1H), 8.42 (dd, 1H), 7.78 (dt, 1H), 7.41 (m,1H), 7.33 (m, 2H), 7.25 (m, 2H), 7.12 (m, 1H), 4.36 (s, 2H), 3.08 (m,4H), 1.77 (m, 2H), 1.5-1.2 (m, 6H).

Example 77N-(Benzyloxy)-N-methyl-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1077)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(benzyloxy)-N-methylhexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.42 (dd, 1H), 7.79 (dt, 1H), 7.40 (m,6H), 4.94 (s, 2H), 4.36 (s, 2H), 3.15 (m, 4H), 2.92 (s, 3H), 1.86 (m,2H), 1.49 (m, 4H), 1.37 (m, 2H).

Example 78N-(Benzyloxy)-N-(2-morpholinoethyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1078)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(benzyloxy)-N-(2-morpholinoethyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.42 (dd, 1H), 7.79 (dt, 1H), 7.40 (m,6H), 5.06 (s, 2H), 4.36 (s, 2H), 3.68 (m, 4H), 3.40 (t, 2H), 3.22 (t,2H), 3.14 (t, 2H), 2.53 (t, 2H), 2.46 (t, 4H), 1.88 (m, 2H), 1.51 (m,4H), 1.39 (m, 2H).

Example 79N-(4-Chlorophenyl)-N-methyl-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1079)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(4-chlorophenyl)-N-methylhexane-1-sulfonamide (see, e.g., WO2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.42 (dd, 1H), 7.78 (dt, 1H), 7.42 (m,5H), 4.36 (s, 2H), 3.32 (s, 3H), 3.11 (m, 4H), 1.76 (m, 2H), 1.46 (m,4H), 1.35 (m, 2H).

Example 80N-(4-Chlorophenyl)-N-(2-morpholinoethyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1080)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(4-chlorophenyl)-N-(2-morpholinoethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.42 (dd, 1H), 7.77 (m, 1H), 7.44 (m,5H), 4.36 (s, 2H), 3.85 (m, 2H), 3.63 (m, 4H), 3.14 (m, 4H), 2.44 (m,6H), 1.79 (m, 2H), 1.47 (m, 4H), 1.36 (m, 2H).

Example 81N-Cyclohexyl-N-(3-morpholinopropyl)-6-(3-(pyridin-4-ylthioureido)hexane-1-sulfonamideoxalate (Compound 1081)

General procedure 3. Starting materials: 4-pyridylamine and6-amino-N-cyclohexyl-N-(3-morpholinopropyl)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (400 MHz, DMSO-d₆): δ 10.16 (bs, 1H), 8.53 (bs, 1H), 8.38 (d,2H), 7.67 (d, 2H), 3.70 (bs, 4H), 3.51-3.36 (m, 3H), 3.13 (t, 2H), 3.02(t, 2H), 2.85 (bs, 4H), 2.73 (t, 2H), 1.86-1.20 (m, 19H), 1.15-1.00 (m,1H).

Example 82N-Cyclopentyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-4-ylthioureido)hexane-1-sulfonamide(Compound 1082)

General procedure 3. Starting materials: 4-pyridylamine and6-amino-N-cyclopentyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (400 MHz, DMSO-d₆): δ 10.29 (bs, 1H), 8.63 (bs, 1H), 8.41 (d,2H), 7.75-7.70 (m, 2H), 4.12 (t, 2H), 3.94 (m, 1H), 3.66-3.60 (m, 4H),3.48 (m, 2H), 3.19 (t, 2H), 2.78 (t, 2H), 2.65 (bs, 4H), 1.91-1.80 (m,2H), 1.80-1.68 (m, 4H), 1.68-1.61 (m, 2H), 1.57 (m, 2H), 1.52-1.40 (m,4H), 1.40-1.29 (m, 2H).

Example 83N-Cyclopentyl-N-(2-morpholinoethoxy)-5-(3-(pyridin-4-ylthioureido)pentane-1-sulfonamideoxalate (Compound 1083)

General procedure 3. Starting materials: 4-pyridylamine and5-amino-N-cyclopentyl-N-(2-morpholinoethoxy)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (400 MHz, DMSO-d₆): δ 10.52 (bs, 1H), 8.81 (bs, 1H), 8.44-8.38(m, 2H), 7.76 (d, 2H), 4.13 (t, 2H), 3.94 (m, 1H), 3.66-3.60 (m, 4H),3.49 (m, 2H), 3.21 (t, 2H), 2.80 (t, 2H), 2.71-2.62 (m, 4H), 1.92-1.69(m, 6H), 1.69-1.55 (m, 4H), 1.55-1.40 (m, 4H).

Example 84N-Cyclopentyl-N-(2-morpholinoethoxy)-5-(3-(pyridin-4-ylureido)pentane-1-sulfonamide(Compound 1084)

General procedure 1. Starting materials: 4-pyridylamine and5-amino-N-cyclopentyl-N-(2-morpholinoethoxy)pentane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (400 MHz, CDCl₃): δ 8.37 (d, 2H), 7.46 (s, 1H), 7.34 (d, 2H),5.33 (t, 1H), 4.19 (bs, 2H), 4.01 (m, 1H), 3.71 (t, 4H), 3.28 (m, 2H),3.09 (bs, 2H), 2.63 (t, 2H), 2.52 (t, 4H), 1.99-1.63 (m, 8H), 1.63-1.46(m, 6H).

Example 85 Ethylmorpholino(6-(3-(pyridin-4-ylthioureido)hexyl)phosphinate oxalate(Compound 1085)

General procedure 3. Starting materials: 4-pyridylamine and ethyl6-aminohexyl(morpholino)phosphinate (see, e.g., WO 2009/086835).

¹H-NMR (400 MHz, DMSO-d₆): δ 10.32 (bs, 1H), 8.65 (bs, 1H), 8.41 (d,2H), 7.77-7.72 (m, 2H), 3.81-4.05 (m, 4H), 3.47 (m, 2H), 3.29-3.19 (m,2H), 1.82-1.43 (m, 10H), 1.43-1.27 (m, 4H), 1.22 (t, 3H).

Example 86 Ethyl morpholino(6-(3-(pyridin-4-ylureido)hexyl)phosphinate(Compound 1086)

General procedure 1. Starting materials: 4-pyridylamine and ethyl6-aminohexyl(morpholino)phosphinate (see, e.g., WO 2009/086835).

¹H-NMR (400 MHz, DMSO-d₆): δ 9.76 (bs, 1H), 8.36 (d, 2H), 7.57 (d, 2H),6.93 (t, 1H), 4.04-3.88 (m, 2H), 3.88-3.81 (m, 2H), 3.29-3.16 (m, 2H),3.09 (m, 2H), 1.81-1.16 (m, 14H), 1.21 (t, 3H).

Example 87N-(cyclohexylmethoxy)-N-(2-fluoroethyl)-6-(3-pyridin-4-ylthioureido)hexane-1-sulfonamide(Compound 1087)

General procedure 3. Starting materials: 4-pyridylamine and6-amino-N-(cyclohexylmethoxy)-N-(2-fluoroethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.35 (m, 2H), 7.72 (m, 2H), 4.62 (dt, 2H), 3.88 (d,2H), 3.60 (m, 3H), 3.51 (t, 1H), 3.21 (m, 2H), 1.91 (m, 2H), 1.8-1.1 (m,15H), 1.05 (m, 2H).

Example 88N-(cyclohexylmethoxy)-N-(2-fluoroethyl)-6-(3-pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1088)

General procedure 1. Starting materials: 4-pyridylamine and6-amino-N-(cyclohexylmethoxy)-N-(2-fluoroethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.27 (m, 2H), 7.46 (m, 2H), 4.61 (dt, 2H), 3.88 (d,2H), 3.55 (dt, 2H), 3.21 (m, 4H), 1.89 (m, 2H), 1.8-1.1 (m, 15H), 1.03(m, 2H).

Example 89N-(cyclohexylmethoxy)-N-(2-fluoroethyl)-6-(3-(pyridin-3-ylmethyl)ureido)hexane-1-sulfonamide(Compound 1089)

General procedure 2. Starting materials: 3-picolylamine and6-amino-N-(cyclohexylmethoxy)-N-(2-fluoroethyl)hexane-1-sulfonamide(see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.42 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.62 (dt, 2H), 4.37 (s, 2H), 3.88 (d, 2H), 3.55 (dt, 2H), 3.17 (m,4H), 1.95-1.05 (m, 19H).

Example 90N-Cyclopentyl-N-(2-morpholinoethoxy)-6-(3-(pyridin-4-ylureido)hexane-1-sulfonamide(Compound 1090)

General procedure 1. Starting materials: 4-pyridylamine and6-amino-N-cyclopentyl-N-(2-morpholinoethoxy)hexane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (400 MHz, CDCl₃): δ 8.38 (m, 2H), 7.34 (m, 2H), 7.24 (s, 1H),5.11 (t, 1H), 4.19 (bs, 2H), 4.01 (m, 1H), 3.71 (t, 4H), 3.28 (m, 2H),3.09 (bs, 2H), 2.62 (t, 2H), 2.51 (t, 4H), 1.96-1.66 (m, 8H), 1.60-1.46(m, 6H), 1.39 (m, 2H).

Example 91N-Cyclopentyl-N-(3-morpholinopropyl)-4-(3-(pyridin-3-ylmethyl)ureido)butane-1-sulfonamide(Compound 1091)

General procedure 2. Starting materials: 3-picolylamine and4-amino-N-cyclopentyl-N-(3-morpholinopropyl)butane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 4.06 (m, 1H), 3.70 (t, 4H), 3.19 (m, 4H), 3.06 (m,2H), 2.47 (t, 4H), 2.38 (t, 2H), 2.0-1.5 (m, 14H).

Example 92N-Cyclobutyl-N-(3-morpholinopropyl)-4-(3-(pyridin-3-ylmethyl)ureido)butane-1-sulfonamide(Compound 1092)

General procedure 2. Starting materials: 3-picolylamine and4-amino-N-cyclobutyl-N-(3-morpholinopropyl)butane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.41 (m,1H), 4.37 (s, 2H), 4.19 (m, 1H), 3.71 (t, 4H), 3.28 (m, 2H), 3.18 (m,2H), 3.00 (m, 2H), 2.48 (t, 4H), 2.40 (t, 2H), 2.19 (m, 4H), 1.9-1.5 (m,8H).

Example 93N-Cyclopentyl-N-(3-morpholinopropyl)-4-(3-pyridin-4-ylthioureido)butane-1-sulfonamide(Compound 1093)

General procedure 3. Starting materials: 4-aminopyridine and4-amino-N-cyclopentyl-N-(3-morpholinopropyl)butane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.37 (m, 2H), 7.73 (m, 2H), 4.08 (m, 1H), 3.70 (m,6H), 3.17 (m, 4H), 2.47 (t, 4H), 2.39 (t, 2H), 2.0-1.5 (m, 14H).

Example 94N-Cyclobutyl-N-(3-morpholinopropyl)-4-(3-pyridin-4-ylthioureido)butane-1-sulfonamide(Compound 1094)

General procedure 3. Starting materials: 4-aminopyridine and4-amino-N-cyclobutyl-N-(3-morpholinopropyl)butane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.36 (m, 2H), 7.72 (m, 2H), 4.21 (m, 1H), 3.70 (m,6H), 3.30 (t, 2H), 3.08 (m, 2H), 2.48 (t, 4H), 2.40 (t, 2H), 2.20 (m,4H), 1.82 (m, 6H), 1.66 (m, 2H).

Example 95N-Cyclopentyl-N-(3-morpholinopropyl)-4-(3-(2-(pyridin-3-yl)ethylureido)butane-1-sulfonamide(Compound 1095)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine and4-amino-N-cyclopentyl-N-(3-morpholinopropyl)butane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.43 (d, 1H), 8.40 (dd, 1H), 7.75 (dt, 1H), 7.40 (m,1H), 4.07 (m, 1H), 3.69 (m, 4H), 3.39 (t, 2H), 3.17 (m, 4H), 3.06 (m,2H), 2.84 (t, 2H), 2.46 (t, 4H), 2.38 (t, 2H), 2.0-1.5 (m, 14H).

Example 96N-Cyclobutyl-N-(3-morpholinopropyl)-4-(3-(2-(pyridin-3-yl)ethylureido)butane-1-sulfonamide(Compound 1096)

General procedure 2. Starting materials: 2-(pyridin-3-yl)ethanamine and4-amino-N-cyclobutyl-N-(2-morpholinopropyl)butane-1-sulfonamide (see,e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.43 (d, 1H), 8.40 (dd, 1H), 7.76 (dt, 1H), 7.40 (m,1H), 4.21 (m, 1H), 3.70 (m, 4H), 3.40 (t, 2H), 3.30 (t, 2H), 3.14 (t,2H), 3.00 (m, 2H), 2.84 (t, 2H), 2.47 (t, 4H), 2.41 (t, 2H), 2.21 (m,4H), 1.9-1.5 (m, 8H).

Example 97 1-(6-(morpholinosulfonyl)hexyl)-3-(pyridin-3-ylmethyl)urea(Compound 1097)

General procedure 2. Starting materials: 3-picolylamine and6-(morpholinosulfonyl)hexan-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.40 (m,1H), 4.37 (s, 2H), 3.73 (t, 4H), 3.25 (t, 4H), 3.15 (t, 2H), 3.03 (m,2H), 1.80 (m, 2H), 1.55-1.25 (m, 6H).

Example 98 1-(6-(azepan-1-ylsulfonyl)hexyl)-3-(pyridin-3-ylmethyl)urea(Compound 1098)

General procedure 2. Starting materials: 3-picolylamine and6-(azepan-1-ylsulfonyl)hexan-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 3.37 (m, 4H), 3.15 (t, 4H), 3.03 (m, 2H), 1.76 (m,6H), 1.66 (m, 4H), 1.6-1.25 (m, 6H).

Example 991-(pyridin-3-ylmethyl)-3-(6-(pyrrolidin-1-ylsulfonyl)hexyl)urea(compound 1099)

General procedure 2. Starting materials: 3-picolylamine and6-(pyrrolidin-1-ylsulfonyl)hexan-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.49 (d, 1H), 8.43 (dd, 1H), 7.79 (dt, 1H), 7.42 (m,1H), 4.37 (s, 2H), 3.34 (m, 4H), 3.15 (t, 4H), 3.06 (m, 2H), 1.95 (m,4H), 1.79 (m, 2H), 1.6-1.25 (m, 6H).

Example 100 1-(6-(piperidin-1-ylsulfonyl)hexyl)-3-(pyridin-4-yl)thiourea(Compound 1100)

General procedure 3. Starting materials: 4-aminopyridine and6-(piperidin-1-ylsulfonyl)hexan-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.35 (m, 2H), 7.73 (m, 2H), 3.62 (t, 2H), 3.24 (m,4H), 3.01 (m, 2H), 1.82 (m, 2H), 1.8-1.35 (m, 12H).

Example 101 1-(6-(morpholinosulfonyl)hexyl)-3-(pyridin-4-yl)thiourea(Compound 1101)

General procedure 3. Starting materials: 4-aminopyridine and6-(morpholinosulfonyl)hexan-1-amine (see, e.g., WO 2009/086835).

¹H-NMR (CD₃OD): δ 8.35 (m, 2H), 7.72 (m, 2H), 4.11 (t, 2H), 3.62 (t,2H), 3.37 (t, 2H), 3.22 (m, 2H), 1.88 (m, 4H), 1.71 (m, 4H), 1.52 (m,4H).

Example 102 In Vitro Cell Proliferation Assay (WST-1 Assay)

A2780 cells were seeded in 96-well plates at 3×10³ cells/well in 100 μLof culture medium, 8 wells were left empty for media only controls.

After 24 h the compound titrations were performed, in a separatedilution plate, by serially diluting the compounds of general formula(I) in culture medium. A 100 μL of each dilution was added to the platedcells, this was done in triplicate, and controls (e.g. DMSO and blanks)were included. The plates were incubated for 24 h at 37° C. in a CO₂incubator. The compound titrations were repeated in a separate dilutionplate after 24 h. The media plus compound from the assay plates werethen aspirated. A 100 μL of media was then added to all wells, followedby 100 μL of each compound dilution. The plates were incubated for afurther 48 h at 37° C. in a CO₂ incubator (total incubation time 72 h).The number of viable cells was then assessed using Cell ProliferationReagent WST-1. 10 μL of WST-1 reagent added to each well and incubatedfor one to four hours at 37° C. in CO₂ incubator. The absorbance wasmeasured (450 nm/690 nm).

The activity of compounds of general formula (I) in reducing the numberof viable cells was calculated as:

% activity=[(S ^(c) −B)/(S ^(o) −B)]×100

S^(c) denotes signal measured in the presence of test compound, S^(o)denotes signal detected in the absence of compound, and B denotesbackground signal, measured in blank wells containing medium only.Analyse data using GraphPad Prism.

Results can be seen in Table 1.

TABLE 1 In vitro cell proliferation assay (WST-1 assay as described inExample 102) IC₅₀ (nM) for Compound No. A2780 FK866: (APO866,(E)-N-(5-(1-benzoyl- 0.1 piperidin-4-yl)pentyl)-3-(pyridine-3-yl)-acrylamide) (WO 97/48695) Compound 1001 13.5 Compound 1002 1.49 Compound1005 0.34 Compound 1007 0.98 Compound 1008 0.23 Compound 1009 0.33Compound 1013 0.11 Compound 1015 0.89 Compound 1018 14.0 Compound 10201.34 Compound 1022 2.23 Compound 1026 0.23 Compound 1031 0.13 Compound1032 14.14 Compound 1042 6.64 Compound 1043 0.37 Compound 1049 0.60Compound 1056 0.58 Compound 1058 0.63 Compound 1063 1.55 Compound 10640.55 Compound 1065 0.22 Compound 1066 0.27 Compound 1067 0.79 Compound1069 3.04 Compound 1072 2.40 Compound 1075 1.64 Compound 1076 5.40Compound 1078 0.46 Compound 1081 0.83 Compound 1082 0.053 Compound 10833.92 Compound 1085 6.18 Compound 1087 1.36 Compound 1088 0.13 Compound1089 2.04 Compound 1090 0.15

1. A compound of the formula (I)

wherein X is selected from ═O, ═S, ═NH, ═NOH and ═NO-Me; A is selectedfrom —C(═O)—, —S(═O)₂—, —C(═S)— and —P(═O)(R⁵)—, wherein R⁵ is selectedfrom C₁₋₆-alkyl, C₁₋₆-alkoxy and hydroxy; B is selected from a singlebond, —(CH₂)₃₋₆—, —O—, and —O—(CH₂)₂₋₅—; D is selected from a singlebond, —O—, —CR⁷R⁸— and —NR⁹, wherein R⁷, R⁸ and R⁹ are independentlyselected from hydrogen, optionally substituted C₁₋₁₂-alkyl, optionallysubstituted C₁₋₁₂-alkenyl, optionally substituted aryl, optionallysubstituted heterocyclyl, and optionally substituted heteroaryl; m is aninteger of 0-12 and n is an integer of 0-12, wherein the sum m+n is1-20; p is an integer of 0-4; R¹ is selected from optionally substitutedheteroaryl; R² is selected from hydrogen, optionally substitutedC₁₋₁₂-alkyl, optionally substituted C₃₋₁₂-cycloalkyl,—[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl), optionallysubstituted C₁₋₁₂-alkenyl, optionally substituted aryl, optionallysubstituted heterocyclyl, and optionally substituted heteroaryl; and R³is selected from optionally substituted C₁₋₁₂-alkyl, optionallysubstituted C₃₋₁₂-cycloalkyl, —[CH₂CH₂O]₁₋₁₀-(optionally substitutedC₁₋₆-alkyl), optionally substituted C₁₋₁₂-alkenyl, optionallysubstituted aryl, optionally substituted heterocyclyl, and optionallysubstituted heteroaryl; or R² and R³ together with the intervening atoms(i.e. —N—B—) form an optionally substituted N-containing heterocyclic orheteroaromatic ring; each of R⁴ and R⁴* is independently selected fromhydrogen, optionally substituted C₁₋₁₂-alkyl and optionally substitutedC₁₋₁₂-alkenyl; with the provisos that R¹ is not optionally substitutedthiazol-2-yl when p is 0; and with the proviso that the compound is notphenyl-NH—C(═O)—(CH₂)₅—NH—C(═S)—NH-(4-pyridyl); and pharmaceuticallyacceptable salts thereof, and prodrugs thereof.
 2. The compoundaccording to claim 1, wherein X is selected from ═O and ═S.
 3. Thecompound according to claim 1, wherein B is —O—.
 4. The compoundaccording to claim 1, wherein A is selected from —S(═O)₂— and —C(═O). 5.The compound according to claim 2, wherein D is a single bond.
 6. Thecompound according to claim 1, wherein B is selected from —(CH₂)₃₋₆— and—O—(CH₂)₂₋₅—.
 7. The compound according to claim 6, wherein A is—S(═O)₂—.
 8. The compound according to claim 1, wherein D is selectedfrom a single bond, —O—, and —NR⁹.
 9. The compound according to claim 1,wherein R¹ is selected from optionally substituted pyridin-4-yl,optionally substituted pyrimidin-4-yl, optionally substituted1,2,4-triazin-3-yl, optionally substituted isoxazol-4-yl, optionallysubstituted pyrazin-2-yl, and optionally substituted picolyl.
 10. Thecompound according to claim 1, wherein p is 0-2.
 11. The compoundaccording to claim 10, wherein p is 0 and R¹ is pyridine-4-yl.
 12. Thecompound according to claim 1, wherein m is an integer of 0-10 and n isan integer of 0-10, wherein the sum m+n is 1-12.
 13. The compoundaccording to claim 12, wherein m is an integer of 2-8 and n is
 0. 14.The compound according to claim 1, wherein at least one of R² and R³includes a carbocyclic ring, heterocyclic ring or a heteroaromatic ring,or R² and R³ together with the intervening atoms form an optionallysubstituted N-containing heterocyclic or heteroaromatic ring.
 15. Thecompound according to claim 14, wherein R² and R³ together with theintervening atoms form an optionally substituted N,O-containingheterocyclic or heteroaromatic ring.
 16. The compound according to claim1, wherein X is selected from ═O and ═S; A is selected from —C(═O)— and—S(═O)₂—; B is selected from —O—, —(CH₂)₃₋₆— and —O—(CH₂)₂₋₅—; D isselected from a single bond, —O—, and —NR⁹; m is an integer of 2-8 and nis 0; p is an integer of 0-2; R² is selected from hydrogen, optionallysubstituted C₃₋₁₂-cycloalkyl, —[CH₂CH₂O]₁₋₁₀-(optionally substitutedC₁₋₆-alkyl), —(CH₂)₀₋₂-(optionally substituted aryl),—(CH₂)₀₋₂-(optionally substituted heteroaryl) and —(CH₂)₀₋₂-(optionallysubstituted heterocyclyl); R³ is selected from optionally substitutedC₃₋₁₂-cycloalkyl, —[CH₂CH₂O]₁₋₁₀-(optionally substituted C₁₋₆-alkyl),optionally substituted C₁₋₁₂-alkenyl, optionally substituted aryl,optionally substituted heterocyclyl, and optionally substitutedheteroaryl; R⁴ is selected from hydrogen, optionally substitutedC₃₋₁₂-cycloalkyl, —(CH₂)O₂-(optionally substituted aryl),—(CH₂)₀₋₂-(optionally substituted heteroaryl) and —(CH₂)₀₋₂-(optionallysubstituted heterocyclyl); and R⁴* is hydrogen.
 17. The compoundaccording to claim 1, which is selected from compounds 1001-1101:Compound Structure
 1001.


1002.


1003.


1004.


1005.


1006.


1007.


1008.


1009.


1010.


1011.


1012.


1013.


1014.


1015.


1016.


1017.


1018.


1019.


1020.


1021.


1022.


1023.


1024.


1025.


1026.


1027.


1028.


1029.


1030.


1031.


1032.


1033.


1034.


1035.


1036.


1037.


1038.


1030.


1040.


1041.


1042.


1043.


1044.


1045.


1046.


1047.


1048.


1049.


1050.


1051.


1052.


1053.


1054.


1055.


1056.


1057.


1058.


1059.


1060.


1061.


1062.


1063.


1064.


1065.


1066.


1067.


1068.


1069.


1070.


1071.


1072.


1073.


1074.


1075.


1076.


1077.


1078.


1079.


1080.


1081.


1082.


1083.


1084.


1085.


1086.


1087.


1088.


1089.


1090.


1091.


1092.


1093.


1094.


1095.


1096.


1097.


1098.


1099.


1100.


1101.

18-20. (canceled)
 21. A method of inhibiting the enzymatic activity ofnicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said methodcomprising the step of administering to said mammal a pharmaceuticallyrelevant amount of a compound as defined in claim
 1. 22. A method oftreating a disease or condition caused by an elevated level ofnicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said methodcomprising the step of administering to said mammal a pharmaceuticallyrelevant amount of a compound as defined in claim
 1. 23. The methodaccording to claim 22, wherein the compound is administered incombination with a DNA damaging agent.
 24. The method according to claim22, wherein said disease or condition is one or more selected from thegroup consisting of rheumatoid arthritis, inflammatory bowel disease,asthma, COPD (chronic obstructive pulmonary disease), osteoarthritis,osteoporosis, fibrotic diseases, dermatosis, psoriasis, atopicdermatitis, ultra-violet induced skin damage, autoimmune diseases,systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis,ankylosing spondylitis, tissue rejection, organ rejection, Alzheimer'sdisease, stroke, atherosclerosis, restenosis, diabetes,glomerulonephritis, breast cancer, prostate cancer, lung cancer, coloncancer, cervix cancer, ovary cancer, skin cancer, CNS cancer, bladdercancer, pancreas cancer, leukaemia, lymphoma or Hodgkin's disease,cachexia, inflammation associated with infection, Acquired ImmuneDeficiency Syndrome (AIDS), adult respiratory distress syndrome, andataxia telangiectasia.